記述言語：英語   掲載種別：研究論文（学術雑誌）  

The majority of the conventional techniques that are utilized for investigating the pathogenesis of cardiovascular disease in preclinical animal models do not permit microlevel assessment of in situ cardiomyocyte and microvascular functions. Therefore, it has been difficult to establish whether cardiac dysfunction in complex multiorgan disease states, such as heart failure with preserved ejection fraction and pulmonary hypertension, have their origins in microvascular dysfunction or rather in the cardiomyocyte. Herein, we describe our approach of utilizing synchrotron radiation microangiography to, first, ascertain whether the growth hormone secretagogue (GHS) hexarelin is a vasodilator in the coronary circulation of normal and anesthetized Sprague-Dawley rats, and next investigate if hexarelin is able to prevent the pathogenesis of right ventricle (RV) dysfunction in pulmonary hypertension in the sugen chronic hypoxia model rat. We show that acute hexarelin administration evokes coronary microvascular dilation through GHS-receptor 1a and nitric oxide, and through endothelium-derived hyperpolarization. Previous work indicated that chronic exogenous administration of ghrelin largely prevented the pathogenesis of pulmonary hypertension in chronic hypoxia and in monocrotaline models. Unexpectedly, chronic hexarelin administration prior to sugen chronic hypoxia did not prevent RV hypertrophy or RV cardiomyocyte relaxation impairment. Small-angle X-ray scattering revealed that super relaxed myosin filaments contributed to diastolic dysfunction, and that length-dependent activation might contribute to sustained contractility of the RV. Thus, synchrotron-based imaging approaches can reveal novel insights into cardiac and coronary functions in vivo.

DOI： 10.3389/fphys.2021.766818

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vagal nerve stimulation (VNS) has been explored as a potential therapy for chronic heart failure. The contribution of the afferent pathway to myocardial interstitial acetylcholine (ACh) release during VNS has yet to be clarified. In seven anesthetized Wistar-Kyoto rats, we implanted microdialysis probes in the left ventricular free wall and measured the myocardial interstitial ACh release during right VNS with the following combinations of stimulation frequency (F in Hz) and voltage readout (V in volts): F0V0 (no stimulation), F5V3, F20V3, F5V10, and F20V10. F5V3 did not affect the ACh level. F20V3, F5V10, and F20V10 increased the ACh level to 2.83 ± 0.47 (P < 0.01), 4.31 ± 1.09 (P < 0.001), and 4.33 ± 0.82 (P < 0.001) nM, respectively, compared with F0V0 (1.76 ± 0.22 nM). After right vagal afferent transection (rVAX), F20V3 and F20V10 increased the ACh level to 2.90 ± 0.53 (P < 0.001) and 3.48 ± 0.63 (P < 0.001) nM, respectively, compared with F0V0 (1.61 ± 0.19 nM), but F5V10 did not (2.11 ± 0.24 nM). The ratio of the ACh levels after rVAX relative to before was significantly <100% in F5V10 (59.4 ± 8.7%) but not in F20V3 (102.0 ± 8.7%). These results suggest that high-frequency and low-voltage stimulation (F20V3) evoked the ACh release mainly via direct activation of the vagal efferent pathway. By contrast, low-frequency and high-voltage stimulation (F5V10) evoked the ACh release in a manner dependent on the vagal afferent pathway.

DOI： 10.1152/ajpregu.00080.2020

PubMed

researchmap

記述言語：英語  

BACKGROUND: As severe acute hypoxemia produces a rapid inhibition of the respiratory neuronal activity through a nonopioid mechanism, we have investigated in adult rats the effects of hypoxemia after fentanyl overdose-induced apnea on (1) autoresuscitation and (2) the antidotal effects of naloxone. METHODS: In nonsedated rats, the breath-by-breath ventilatory and pulmonary gas exchange response to fentanyl overdose (300 µg · kg · min iv in 1 min) was determined in an open flow plethysmograph. The effects of inhaling air (nine rats) or a hypoxic mixture (fractional inspired oxygen tension between 7.3 and 11.3%, eight rats) on the ability to recover a spontaneous breathing rhythm and on the effects of naloxone (2 mg · kg) were investigated. In addition, arterial blood gases, arterial blood pressure, ventilation, and pulmonary gas exchange were determined in spontaneously breathing tracheostomized urethane-anesthetized rats in response to (1) fentanyl-induced hypoventilation (7 rats), (2) fentanyl-induced apnea (10 rats) in air and hyperoxia, and (3) isolated anoxic exposure (4 rats). Data are expressed as median and range. RESULTS: In air-breathing nonsedated rats, fentanyl produced an apnea within 14 s (12 to 29 s). A spontaneous rhythmic activity always resumed after 85.4 s (33 to 141 s) consisting of a persistent low tidal volume and slow frequency rhythmic activity that rescued all animals. Naloxone, 10 min later, immediately restored the baseline level of ventilation. At fractional inspired oxygen tension less than 10%, fentanyl-induced apnea was irreversible despite a transient gasping pattern; the administration of naloxone had no effects. In sedated rats, when PaO2 reached 16 mmHg during fentanyl-induced apnea, no spontaneous recovery of breathing occurred and naloxone had no rescuing effect, despite circulation being maintained. CONCLUSIONS: Hypoxia-induced ventilatory depression during fentanyl induced apnea (1) opposes the spontaneous emergence of a respiratory rhythm, which would have rescued the animals otherwise, and (2) prevents the effects of high dose naloxone.

DOI： 10.1097/ALN.0000000000003156

PubMed

researchmap

記述言語：英語  

BACKGROUND: Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl). METHODS: Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting. RESULTS: We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably. CONCLUSIONS: In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.

DOI： 10.1186/s12933-020-01000-z

PubMed

researchmap

記述言語：英語  

Cardiac microdialysis allows the assessment of cardiac efferent vagal nerve activity from myocardial interstitial acetylcholine (ACh) levels with minimal influence on the neural control of the heart; however, a total picture of the baroreflex-mediated myocardial interstitial ACh release including the threshold and saturation pressures has yet to be quantified. In eight anesthetized Wistar-Kyoto rats, we implanted microdialysis probes in the left ventricular free wall and measured the myocardial interstitial ACh release simultaneously with efferent sympathetic nerve activity (SNA) during a carotid sinus baroreceptor pressure input between 60 and 180 mm Hg. The baroreflex-mediated ACh release approximated a positive sigmoid curve, and its threshold and saturation pressures were not significantly different from those of an inverse sigmoid curve associated with the baroreflex-mediated SNA response (threshold: 94.3 ± 8.6 vs. 99.3 ± 6.0 mm Hg; saturation: 150.0 ± 10.3 vs. 158.8 ± 5.8 mm Hg). The sympathetic and vagal systems have certain levels of activities across most of the normal pressure range.

DOI： 10.1016/j.autneu.2020.102657

PubMed

researchmap

記述言語：英語  

Coronary microvessel endothelial dysfunction and nitric oxide (NO) depletion contribute to elevated passive tension of cardiomyocytes, diastolic dysfunction and predispose the heart to heart failure with preserved ejection fraction. We examined if diastolic dysfunction at the level of the cardiomyocytes precedes coronary endothelial dysfunction in prediabetes. Further, we determined if myofilaments other than titin contribute to impairment. Utilizing synchrotron microangiography we found young prediabetic male rats showed preserved dilator responses to acetylcholine in microvessels. Utilizing synchrotron X-ray diffraction we show that cardiac relaxation and cross-bridge dynamics are impaired by myosin head displacement from actin filaments particularly in the inner myocardium. We reveal that increased PKC activity and mitochondrial oxidative stress in cardiomyocytes contributes to rho-kinase mediated impairment of myosin head extension to actin filaments, depression of soluble guanylyl cyclase/PKG activity and consequently stiffening of titin in prediabetes ahead of coronary endothelial dysfunction.

DOI： 10.1016/j.yjmcc.2019.10.005

PubMed

researchmap

DOI： 10.14814/phy2.14297

PubMed

researchmap

記述言語：英語  

Metabolic syndrome is a common risk factor in chronic kidney disease. We investigated whether liraglutide [(LIRA), a glucagon-like peptide-1 receptor (GLP-1R) agonist] treatment improved renal vascular function and renal remodeling in male Zucker rats on a high-salt diet (6% NaCl). Zucker lean (+/+) and obese (fa/fa) rats (8 weeks old) were treated with vehicle or LIRA (0.1 mg/kg per day) for 8 weeks on a high-salt diet. The glomerular filtration rate (GFR) was measured at 0 and 8 weeks using the fluorescein isothiocyanate/sinistrin method in conscious rats. We used X-ray microangiography to measure renal arterial vessel diameter (70-350 µm) and vessel number in vivo in anesthetized rats. Renal protein expression levels of nitrotyrosine, CD-68, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), transforming growth factor-β1, cyclooxygenase-2, and GLP-1R were assessed by western blotting. Renal gene expressions were determined by real-time polymerase chain reaction. In contrast to vehicle-treated rats, fa/fa-LIRA rats improved GFR, nitric oxide (NO)-mediated vasodilation in response to acetylcholine and sodium nitroprusside in small arterial vessels (<200 µm diameter). LIRA treatment increased vessel responsivity to NO donors in comparison with vehicle treatment. Increases in the expressions of proinflammatory, profibrotic, and oxidative stress related genes in fa/fa rats relative to +/+ were unaltered by LIRA, other than a trend toward attenuation of VCAM-1 gene expression. However, LIRA treatment increased protein expressions of eNOS (P = 0.014) and VEGF (P = 0.063), while reducing glomerular macrophage infiltration in comparison with vehicle-treated fa/fa rats. Low-dose LIRA treatment improved renal vascular function through amelioration of vascular dysfunction and improved NO-mediated dilation of small intrarenal arteries and arterioles and a reduction in renal inflammation.

DOI： 10.1124/jpet.118.254821

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.autneu.2019.02.005

PubMed

researchmap

DOI： 10.1016/j.nbd.2019.05.013

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/1074248419829168

PubMed

researchmap

DOI： 10.1016/j.autneu.2018.09.001

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ghrelin is a small peptide with important roles in the regulation of appetite, gut motility, glucose homeostasis as well as cardiovascular protection. This review highlights the role that acyl ghrelin plays in maintaining normal endothelial function by maintaining the balance of vasodilator-vasoconstrictor factors, inhibiting inflammatory cytokine production and immune cell recruitment to sites of vascular injury and by promoting angiogenesis.

DOI： 10.1530/VB-19-0024

PubMed

researchmap

DOI： 10.1007/s12012-018-9454-2

PubMed

researchmap

DOI： 10.1080/15563650.2018.1429615

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

The regions of the olfactory epithelium affected by hydrogen sulfide (H2S) toxicity in the rat present a striking similarity with the developmental olfactory zone 1 described in the mouse. This zone which is the only region containing neurons expressing NAD(P)H quinone dehydrogenase 1 (NQO1) is involved in complex behavioral responses in rodents, and other mammals, triggered by specific olfactory stimuli. We therefore sought to determine whether (1) olfactory neurons expressing NQO1 are located in the same regions in the rats and in the mice and (2) there is an overlap between olfactory neurons expressing this protein and those affected by the toxicity of H2S. Rats were exposed to H2S - 200 ppm during 3 h, three consecutive days- and displayed symmetric acute segmental necrosis of the neurons and sustentacular cells of the olfactory epithelium in the dorsomedial nasal cavity. We found that expression of NQO1 in Sprague-Dawley rats spatially recapitulated that of the mouse. The degree of agreement or overlap between these two populations of neurons (necrosis vs. NQO1 expression) reached 80.2%. Although the underlying mechanisms accounted for the high sensitivity for NQO1 neurons -or the relative protection of non NQO1 neurons- to sulfide toxicity remain to be established, this observation is offering an intriguing approach that could be used to acutely suppress the pool of neural cells in olfactory zone I and to understand the mechanisms of toxicity and protection of other populations of neurons exposed to sulfide. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2017.10.014

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

It has been shown that the size of myocardial infarction in rats created by coronary ligation technique is not uniform, varying from 4% to 65%. We hypothesized that infarct size variability induced by coronary artery ligation might be caused by coronary artery branching pattern. Coronary artery angiography was performed in 50 normal Lewis rats and in chronic myocardial infarction models in which coronary artery was ligated immediately below the left atrial appendage or 2mm distal to the left atrial appendage (n = 25 for each), followed by histological analysis. Unlike the human, the rats had a single major septal artery arising from the proximal part of the left coronary artery (n = 30) or right coronary artery (n = 20). There were three branching patterns of left circumflex artery (LCX): 33 (66%) had LCX branching peripherally from a long left main coronary artery (LMCA), while the remainder 17 (34%) had the LCX branching from the proximal part of the septal artery or a short LMCA. The rats with distal coronary ligation presented myocardial infarction localized to an anterior territory irrespective of LCX branching pattern. In the rats with proximal coronary ligation, 64% (n = 16) had broad myocardial infarction involving the anterior and lateral territories, while the remainder (36%, n = 9) had myocardial infarction localized to an anterior territory with the intact LCX arising proximally from a short LMCA. The interventricular septum was spared from infarction in all rats because of its anatomical location. Infarct size variations were caused not only by ligation site but also by varying LCX branching patterns. There are potential risks to create different sizes of myocardial infarction, particularly when targeting a broad range of myocardial infarction. The territory of the septal artery always appears to be spared from myocardial infarction induced by the coronary ligation technique.

DOI： 10.1371/journal.pone.0183323

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Our objective was to determine how circulatory failure develops following systemic administration of potassium cyanide (KCN). We used a noninhaled modality of intoxication, wherein the change in breathing pattern would not influence the diffusion of CN into the blood, akin to the effects of ingesting toxic levels of CN. In a group of 300 to 400g rats, CN-induced coma (CN i.p., 7mg/kg) produced a central apnea within 2 to 3 min along with a potent and prolonged gasping pattern leading to autoresuscitation in 38% of the animals. Motor deficits and neuronal necrosis were nevertheless observed in the surviving animals. To clarify the mechanisms leading to potential autoresuscitation versus asystole, 12 urethane-anesthetized rats were then exposed to the lowest possible levels of CN exposure that would lead to breathing depression within 7 to 8 min; this dose averaged 0.375mg/kg/min i.v. At this level of intoxication, a cardiac depression developed several minutes only after the onset of the apnea, leading to cardiac asystole as PaO2 reached value approximately 15 Torr, unless breathing was maintained by mechanical ventilation or through spontaneous gasping. Higher levels of KCN exposure in 10 animals provoked a primary cardiac depression, which led to a rapid cardiac arrest by pulseless electrical activity (PEA) despite the maintenance of PaO2 by mechanical ventilation. These effects were totally unrelated to the potassium contained in KCN. It is concluded that circulatory failure can develop as a direct consequence of CN-induced apnea but in a narrow range of exposure. In this low range, maintaining pulmonary gas exchange after exposure, through mechanical ventilation (or spontaneous gasping), can reverse cardiac depression and restore spontaneous breathing. At higher level of intoxication, cardiac depression is to be treated as a specific and spontaneously irreversible consequence of CN exposure, leading to a PEA.

DOI： 10.1097/SHK.0000000000000732

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

In this study, we have tried to characterize the limits of the approach typically used to determine H2S concentrations in the heart based on the amount of H2S evaporating from heart homogenates-spontaneously, after reaction with a strong reducing agent, or in a very acidic solution. Heart homogenates were prepared from male rats in control conditions or after H2S infusion induced a transient cardiogenic shock (CS) or cardiac asystole (CA). Using a method of determination of gaseous H2S with a detection limit of 0.2 nmol, we found that the process of homogenization could lead to a total disappearance of free H2S unless performed in alkaline conditions. Yet, after restoration of neutral pH, free H2S concentration from samples processed in alkaline and nonalkaline milieus were similar and averaged similar to 0.2-0.4 nmol/g in both control and CS homogenate hearts and up to 100 nmol/g in the CA group. No additional H2S was released from control, CS, or CA hearts by using the reducing agent tris(2-carboxyethyl) phosphine or a strong acidic solution (pH &lt; 2) to "free" H2S from combined pools. Of note, the reducing agent DTT produced a significant sulfide artifact and was not used. These data suggest that 1) free H2S found in heart homogenates is not a reflection of H2S present in a "living" heart and 2) the pool of combined sulfides, released in a strong reducing or acidic milieu, does not increase in the heart in a measurable manner even after toxic exposure to sulfide.

DOI： 10.1152/ajpheart.00464.2016

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

We have previously reported that methylene blue (MB) can counteract hydrogen sulfide (H2S) intoxication- induced circulatory failure. Because of the multifarious effects of high concentrations of H2S on cardiac function, as well as the numerous properties of MB, the nature of this interaction, if any, remains uncertain. The aim of this study was to clarify 1) the effects of MB on H2S-induced cardiac toxicity and 2) whether L-type Ca2+ channels, one of the targets of H2S, could transduce some of the counteracting effects of MB. In sedated rats, H2S infused at a rate that would be lethal within 5 min (24 mu M.kg(-1).min(-1)), produced a rapid fall in left ventricle ejection fraction, determined by echocardiography, leading to a pulseless electrical activity. Blood concentrations of gaseous H2S reached 7.09 +/- 3.53 mu M when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and V-O2, allowing the animals to stay alive until the end of H2S infusion. MB also delayed PEA by several minutes following H2S-induced coma and shock in unsedated rats. Applying a solution containing lethal levels of H2S (100 mu M) on isolated mouse cardiomyocytes significantly reduced cell contractility, intracellular calcium concentration ([Ca2+] i) transient amplitudes, and L-type Ca2+ currents (I-Ca) within 3 min of exposure. MB (20 mg/l) restored the cardiomyocyte function, ([Ca2+] i) transient, and I-Ca. The present results offer a new approach for counteracting H2S toxicity and potentially other conditions associated with acute inhibition of L-type Ca2+ channels.

DOI： 10.1152/ajpregu.00527.2015

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：HUMANA PRESS INC  

Hydrogen sulfide (H2S) intoxication produces a rapid cardio-circulatory failure leading to cardiac arrest. In non-lethal forms of sulfide exposure, the presence of a circulatory shock is associated with long-term neurological sequelae. Our aim was to clarify the mechanisms of H2S-induced circulatory failure. In anesthetized, paralyzed, and mechanically ventilated rats, cardiac output, arterial pressure and ventricular pressures were determined while NaHS was infused to increase arterial concentration of soluble H2S (CgH(2)S) from undetectable to levels leading to circulatory failure. Compared to control/saline infusion, blood pressure started to decrease significantly along with a modest drop in peripheral vascular resistance (-19 +/- A 5 %, P &lt; 0.01), when CgH(2)S reached about 1 mu M. As CgH(2)S exceeded 2-3 mu M, parameters of ventricular contractility diminished with no further reduction in peripheral resistance. Whenever H2S exposure was maintained at a higher level (CgH(2)S over 7 mu M), a severe depression of cardiac contractility was observed, leading to asystole within minutes, but with no evidence of peripheral vasoplegia. The immediate and long-term neurological effects of specifically counteracting sulfide-induced cardiac contractility depression following H2S exposure remain to be investigated.

DOI： 10.1007/s12012-015-9309-z

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE PUBL  

Hydrogen sulfide (H2S) is a chemical hazard in the gas and farming industry. As it is easy to manufacture from common chemicals, it has also become a method of suicide. H2S exerts its toxicity through its high affinity with metalloproteins, such as cytochrome c oxidase and possibly via its interactions with cysteine residues of various proteins. The latter was recently proposed to acutely alter ion channels with critical implications for cardiac and brain functions. Indeed, during severe H2S intoxication, a coma, associated with a reduction in cardiac contractility, develops within minutes or even seconds leading to death by complete electromechanical dissociation of the heart. In addition, long-term neurological deficits can develop owing to the direct toxicity of H2S on neurons combined with the consequences of a prolonged apnea and circulatory failure. Here, we review the challenges impeding efforts to offer an effective treatment against H2S intoxication using agents that trap free H2S, and present novel pharmacological approaches aimed at correcting some of the most harmful consequences of H2S intoxication.

DOI： 10.1111/nyas.13015

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ENDOCRINE SOC  

The hormone ghrelin prevents a dangerous increase in cardiac sympathetic nerve activity (SNA) after acute myocardial infarction (MI), although the underlying mechanisms remain unknown. This study aimed to determine whether ghrelin's sympathoinhibitory properties stem either from directly within the central nervous system, or via modulation of specific cardiac vagal inhibitory afferents. Cardiac SNA was recorded in urethane-anesthetized rats for 3 hours after the ligation of the left anterior descending coronary artery (ie, MI). Rats received ghrelin either sc (150 mu g/kg) or intracerebroventricularly (5 mu g/kg) immediately after the MI. In another two groups, the cervical vagi were denervated prior to the MI, followed by sc injection of either ghrelin or placebo. Acute MI induced a 188% increase in cardiac SNA, which was significantly attenuated in ghrelin-treated rats for both sc or intracerebroventricularly administration (36% and 76% increase, respectively). Consequently, mortality (47%) and the incidence of arrhythmic episodes (12 per 2 h) were improved with both routes of ghrelin administration (&lt;13% and less than five per 2 h, respectively). Bilateral vagotomy significantly attenuated the cardiac SNA response to acute MI (99% increase). Ghrelin further attenuated the sympathetic response to MI in vagotomized rats so that the SNA response was comparable between vagotomized and vagal-intact MI rats treated with ghrelin. These results suggest that ghrelin may act primarily via a central pathway within the brain to suppress SNA after MI, although peripheral vagal afferent pathways may also contribute in part. The exact region(s) within the central nervous system whereby ghrelin inhibits SNA remains to be fully elucidated.

DOI： 10.1210/EN.2015-1333

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Context. Hydrogen sulfide (H2S) intoxication produces an acute depression in cardiac contractility-induced circulatory failure, which has been shown to be one of the major contributors to the lethality of H2S intoxication or to the neurological sequelae in surviving animals. Methylene blue (MB), a phenothiazinium dye, can antagonize the effects of the inhibition of mitochondrial electron transport chain, a major effect of H2S toxicity. Objectives. We investigated whether MB could affect the immediate outcome of H2S-induced coma in unanesthetized animals. Second, we sought to characterize the acute cardiovascular effects of MB and two of its demethylated metabolites-azure B and thionine-in anesthetized rats during lethal infusion of H2S. Materials and methods. First, MB (4 mg/kg, intravenous [IV]) was administered in non-sedated rats during the phase of agonal breathing, following NaHS (20 mg/kg, IP)-induced coma. Second, in 4 groups of urethane-anesthetized rats, NaHS was infused at a rate lethal within 10 mm (0.8 mg/min, IV). Whenever cardiac output (CO) reached 40% of its baseline volume, MB, azure B, thionine, or saline were injected, while sulfide infusion was maintained until cardiac arrest occurred. Results. Seventy-five percent of the comatose rats that received saline (n= 8) died within 7 mm, while all the 7 rats that were given MB survived (p=0.007). In the anesthetized rats, arterial, left ventricular pressures and CO decreased during NaHS infusion, leading to a pulseless electrical activity within 530 s. MB produced a significant increase in CO and dP/dt(max) for about 2 min. A similar effect was produced when MB was also injected in the pre-mortem phase of sulfide exposure, significantly increasing survival time. Azure B produced an even larger increase in blood pressure than MB, while thionine had no effect. Conclusion. MB can counteract NaHSinduced acute cardiogenic shock; this effect is also produced by azure B, but not by thionine, suggesting that the presence of methyl groups is a prerequisite for producing this protective effect.

DOI： 10.3109/15563650.2015.1043440

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0131923

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background
Acute hydrogen sulfide (H2S) poisoning produces a coma, the outcome of which ranges from full recovery to severe neurological deficits. The aim of our study was to 1-describe the immediate and long-term neurological effects following H2S-induced coma in un-anesthetized rats, and 2-determine the potential benefit of methylene blue (MB), a compound we previously found to counteract acute sulfide cardiac toxicity.
Methods
NaHS was administered IP in un-sedated rats to produce a coma (n = 34). One minute into coma, the rats received MB (4 mg/kg IV) or saline. The surviving rats were followed clinically and assigned to Morris water maze (MWM) and open field testing then sacrificed at day 7.
Results
Sixty percent of the non-treated comatose rats died by pulseless electrical activity. Nine percent recovered with neurological deficits requiring euthanasia, their brain examination revealed major neuronal necrosis of the superficial and middle layers of the cerebral cortex and the posterior thalamus, with variable necrosis of the caudate putamen, but no lesions of the hippocampus or the cerebellum, in contrast to the typical distribution of post-ischemic lesions. The remaining animals displayed, on average, a significantly less effective search strategy than the control rats (n = 21) during MWM testing. Meanwhile, 75% of rats that received MB survived and could perform the MWM test (P &lt; 0.05 vs non-treated animals). The treated animals displayed a significantly higher occurrence of spatial search than the non-treated animals. However, a similar proportion of cortical necrosis was observed in both groups, with a milder clinical presentation following MB.
Conclusion
In conclusion, in rats surviving H2S induced coma, spatial search patterns were used less frequently than in control animals. A small percentage of rats presented necrotic neuronal lesions, which distribution differed from post-ischemic lesions. MB dramatically improved the immediate survival and spatial search strategy in the surviving rats.

DOI： 10.1371/journal.pone.0131340

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Molecular pathways regulating the development of arterial and venous endothelial cells (ECs) are now well established, but control of parallel arterialvenous alignment is unclear. Here we report that arterial-venous alignment in the skin is determined by apelin receptor (APJ) expression in venous ECs. One of the activators of APJ is apelin. We found that apelin is produced by arterial ECs during embryogenesis, induces chemotaxis of venous ECs, and promotes the production of secreted Frizzled-related protein 1 (sFRP1) by APJ(+) ECs. sFRP1 stimulates matrix metalloproteinase production by Ly6B.2(+) neutrophil-like cells located between the arteries and veins, resulting in remodeling of extracellular matrices to support venous displacement. Moreover, using apelin-or APJ-deficient mice, which exhibit arterial-venous disorganization, we found that arterial-venous alignment is involved in thermoregulation, possibly by regulating countercurrent heat exchange. We hypothesize that the evolution of parallel juxtapositional arterial-venous alignment was an adaptation to reduce body heat loss.

DOI： 10.1016/j.devcel.2015.02.024

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.

DOI： 10.1073/pnas.1424774112

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Vascular function is impaired in patients with diabetes, however diabetic vascular dysfunction is ameliorated by exercise training. We aimed to clarify which hindlimb arterial segments are affected by treadmill running in the hindlimbs of streptozocin-induced type 1 diabetic mice in vivo.
Methods: Mice were divided into 3 groups; healthy control, diabetic control, and diabetic-running groups. The exercise regimen was performed by treadmill level running mice for 60 min/day, for 4 weeks. Thereafter, we examined the vascular response to systemic acetylcholine administration in the left hindlimb of anesthetized-ventilated mice using either 1) X-ray microangiography to visualize the arteries or 2) ultrasonic flowmetry to record the femoral arterial blood flow.
Results: X-ray imaging clearly visualized the hindlimb arterial network (similar to 70-250 mu m diameter). The vasodilator response to acetylcholine was significantly attenuated locally in the arterioles &lt; 100 mu m diameter in the diabetic group of mice compared to the control group of mice. Post-acetylcholine administration, all groups showed an increase in hindlimb vascular conductance, but the diabetic mice showed the smallest increase. Overall, compared to the diabetic mice, the treadmill-running mice exhibited a significant enhancement of the vasodilator response within the arterioles with diabetes-induced vasodilator dysfunction.
Conclusions: Diabetes impaired acetylcholine-induced vasodilator function locally in the arteries &lt; 100 mu m diameter and decreased hindlimb vascular conductance responded to acetylcholine, while regular treadmill running significantly ameliorated the impaired vasodilator function, and enhanced the decreased conductance in the diabetic mice.

DOI： 10.1186/s12933-015-0217-0

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：INFORMA HEALTHCARE  

DOI： 10.3109/15563650.2015.1014908

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cell-sheet transplantation induces angiogenesis for chronic myocardial infarction (MI), though insufficient capillary maturation and paucity of arteriogenesis may limit its therapeutic effects. Omentum has been used clinically to promote revascularization and healing of ischemic tissues. We hypothesized that cell-sheet transplantation covered with an omentum-flap would effectively establish mature blood vessels and improve coronary microcirculation physiology, enhancing the therapeutic effects of cell-sheet therapy. Rats were divided into four groups after coronary ligation; skeletal myoblast cell-sheet plus omentum-flap (combined), cell-sheet only, omentum-flap only, and sham operation. At 4 weeks after the treatment, the combined group showed attenuated cardiac hypertrophy and fibrosis, and a greater amount of functionally (CD31(+)/lectin(+)) and structurally (CD31(+)/α-SMA(+)) mature blood vessels, along with myocardial upregulation of relevant genes. Synchrotron-based microangiography revealed that the combined procedure increased vascularization in resistance arterial vessels with better dilatory responses to endothelium-dependent agents. Serial (13)N-ammonia PET showed better global coronary flow reserve in the combined group, mainly attributed to improvement in the basal left ventricle. Consequently, the combined group had sustained improvements in cardiac function parameters and better functional capacity. Cell-sheet transplantation with an omentum-flap better promoted arteriogenesis and improved coronary microcirculation physiology in ischemic myocardium, leading to potent functional recovery in the failing heart.

DOI： 10.1038/mt.2014.225

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

RATIONALE: We have recently reported that infusion of a solution containing methemoglobin (MetHb) during exposure to hydrogen sulfide results in a rapid and large decrease in the concentration of the pool of soluble/diffusible H2S in the blood. However, since the pool of dissolved H2S disappears very quickly after H2S exposure, it is unclear if the ability of MetHb to "trap" sulfide in the blood has any clinical interest and relevance in the treatment of sulfide poisoning. METHODS: In anesthetized rats, repetition of short bouts of high level of H2S infusions was applied to allow the rapid development of an oxygen deficit. A solution containing MetHb (600 mg/kg) or its vehicle was administered 1 min and a half after the end of H2S intoxication. RESULTS: The injection of MetHb solution increased methemoglobinemia to about 6%, almost instantly, but was unable to affect the blood concentration of soluble H2S, which had already vanished at the time of infusion, or to increase combined H2S. In addition, H2S-induced O2 deficit and lactate production as well as the recovery of carotid blood flow and blood pressure were similar in treated and control animals. CONCLUSION: Our results do not support the view that administration of MetHb or drugs-induced methemoglobinemia during the recovery phase following severe H2S intoxication in sedated rats can restore cellular oxidative metabolism, as the pool of diffusible sulfide, accessible to MetHb, disappears rapidly from the blood after H2S exposure.

DOI： 10.3109/15563650.2014.996570

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Context. Severe H2S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication. Objectives. To determine the time course and the nature of H2S-induced cardiac arrest and the effects of high-dose hydroxocobalamin administered after the end of sulfide exposure. Materials and methods. NaHS was infused in 16 sedated mechanically ventilated sheep to reach concentrations of H2S in the blood, which was previously found to lead to cardiac arrest within minutes following the cessation of H2S exposure. High-dose hydroxocobalamin (5 g) or saline solution was administered intravenously, 1 min after the cessation of NaHS infusion. Results. All animals were still alive at the cessation of H2S exposure. Three animals (18%) presented a cardiac arrest within 90 s and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 min. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g of hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving hydroxocobalamin, as blood lactate remained elevated and even continued to rise after 1 h, despite restored hemodynamics. This, along with an unaltered recovery of H2S kinetics, suggests that hydroxocobalamin did not act through a mechanism of H2S trapping. Conclusion. In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 min after H2S exposure. Very high dose of hydroxocobalamin (5 g), injected very early after the cessation of H2S exposure, improved cardiac contractility and prevented PEA.

DOI： 10.3109/15563650.2014.990976

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COGNIZANT COMMUNICATION CORP  

In vitro expanded beating cardiac myocytes derived from induced pluripotent stem cells (iPSC-CMs) are a promising source of therapy for cardiac regeneration. Meanwhile, the cell sheet method has been shown to potentially maximize survival, functionality, and integration of the transplanted cells into the heart. It is thus hypothesized that transplanted iPSC-CMs in a cell sheet manner may contribute to functional recovery via direct mechanical effects on the myocardial infarction (MI) heart. F344/NJcl-rnu/rnu rats were left coronary artery ligated (n = 30), followed by transplantation of Dsred-labeled iPSC-CM cell sheets of murine origin over the infarct heart surface. Effects of the treatment were assessed, including in vivo molecular/cellular evaluations using a synchrotron radiation scattering technique. Ejection fraction and activation recovery interval were significantly greater from day 3 onward after iPSC-CM transplantation compared to those after sham operation. A number of transplanted iPSC-CMs were present on the heart surface expressing cardiac myosin or connexin 43 over 2 weeks, assessed by immunoconfocal microscopy, while mitochondria in the transplanted iPSC-CMs gradually showed mature structure as assessed by electron microscopy. Of note, X-ray diffraction identified 1,0 and 1,1 equatorial reflections attributable to myosin and actin-myosin lattice planes typical of organized cardiac muscle fibers within the transplanted cell sheets at 4 weeks, suggesting cyclic systolic myosin mass transfer to actin filaments in the transplanted iPSC-CMs. Transplantation of iPSC-CM cell sheets into the heart yielded functional and electrical recovery with cyclic contraction of transplanted cells in the rat MI heart, indicating that this strategy may be a promising cardiac muscle replacement therapy.

DOI： 10.3727/096368914X685799

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Aims: The aim of this study was to elucidate myocardial interstitial serotonin (5-HT) kinetics in the heart, including 5-HT reuptake and enzymatic degradation to 5-hydroxyindole acetic acid (5-HIAA) via monoamine oxidase (MAO).
Main methods: Using microdialysis technique in anesthetized rats, we simultaneously monitored myocardial interstitial levels of 5-HT and its major metabolite, 5-HIAA, in the left ventricle and examined the effects of local administration of a MAO inhibitor, pargyline, or a 5-HT uptake inhibitor, fluoxetine.
Key findings: Pargyline increased dialysate 5-HT concentration from 1.8 +/- 0.3 at baseline to 3.9 +/- 0.5 nM but decreased dialysate 5-HIAA concentration from 20.7 +/- 1.0 at baseline to 15.8 +/- 1.4 nM at 60-80 min of administration. Fluoxetine increased dialysate 5-HT concentration from 1.9 +/- 0.4 at baseline to 6.5 +/- 0.9 nM at 60-80 min of administration, but did not change dialysate 5-HIAA concentration. Local administration of ADP (100 mM) increased dialysate 5-HT and 5-HIAA concentrations. Pargyline did not affect ADP-induced increase in dialysate 5-HT concentration but suppressed ADP-induced increase in dialysate 5-HIAA concentration during 60 min of ADP administration. Fluoxetine increased dialysate 5-HT concentration at 40-60 min of ADP administration, but did not affect ADP-induced increase in dialysate 5-HIAA concentration.
Significance: Simultaneous monitoring of myocardial interstitial 5-HT and 5-HIAA levels provides valuable information on 5-HT kinetics including reuptake and enzymatic degradation by MAO, which play a role in the regulation of myocardial interstitial 5-HT levels at baseline and when 5-HT levels are elevated. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2014.09.019

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Hydrogen sulphide (H2S), a chemical hazard in oil and gas production, has recently become a dreadful method of suicide, posing specific risks and challenges for the first responders. Currently, there is no proven effective treatment against H2S poisoning and its severe neurological, respiratory or cardiac after-effects. We have recently described that H2S is present in various compartments, or pools, in the body during sulphide exposure, which have different levels of toxicity. The general goals of our study were to (1) determine the concentrations and kinetics of the various pools of hydrogen sulphide in the blood, i.e., gaseous (CgH(2)S) versus total sulphide, i.e., reacting with monobromobimane (CMBBH2S), during and following H2S exposure in a small and large mammal and (2) establish the interaction between the pools of H2S and a methemoglobin (MetHb) solution or a high dose of hydroxocobalamin (HyCo). We found that CgH(2)S during and following H2S infusion was similar in sedated sheep and rats at any given rate of infusion/kg and provoked symptoms, i.e., hyperpnea and apnea, at the same CgH(2)S. After H2S administration was stopped, CgH(2)S disappeared within 1 min. CMBBH2S also dropped to 2-3 mu M, but remained above baseline levels for at least 30 min. Infusion of a MetHb solution during H2S infusion produced an immediate reduction in the free/soluble pool of H2S only, whereas CMBBH2S increased by severalfold. HyCo (70 mg/kg) also decreased the concentrations of free/soluble H2S to almost zero; CgH(2)S returned to pre-HyCo levels within a maximum of 20 min, if H2S infusion is maintained. These results are discussed in the context of a relevant scenario, wherein antidotes can only be administered after H2S exposure.

DOI： 10.1093/toxsci/kfu140

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

At birth, the transition to newborn life is triggered by lung aeration, which stimulates a large increase in pulmonary blood flow (PBF). Current theories predict that the increase in PBF is spatially related to ventilated lung regions as they aerate after birth. Using simultaneous phase-contrast X-ray imaging and angiography we investigated the spatial relationships between lung aeration and the increase in PBF after birth. Six near-term (30-day gestation) rabbits were delivered by caesarean section, intubated and an intravenous catheter inserted, before they were positioned for X-ray imaging. During imaging, iodine was injected before ventilation onset, after ventilation of the right lung only, and after ventilation of both lungs. Unilateral ventilation increased iodine levels entering both left and right pulmonary arteries (PAs) and significantly increased heart rate, iodine ejection per beat, diameters of both left and right PAs, and number of visible vessels in both lungs. Within the 6th intercostal space, the mean gray level (relative measure of iodine level) increased from 68.3 +/- 11.6 and 70.3 +/- 7.5%.s to 136.3 +/- 22.6 and 136.3 +/- 23.7%.s in the left and right PAs, respectively. No differences were observed between vessels in the left and right lungs, despite the left lung not initially being ventilated. The increase in PBF at birth is not spatially related to lung aeration allowing a large ventilation/perfusion mismatch, or pulmonary shunting, to occur in the partially aerated lung at birth.

DOI： 10.1152/japplphysiol.01358.2013

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.resp.2014.05.012

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER HEIDELBERG  

Chronic intermittent hypoxia (IH) provokes a centrally mediated increase in sympathetic nerve activity (SNA). Although this sympathetic hyperexcitation has been linked to systemic hypertension, its effect on the pulmonary vasculature is unclear. This study aimed to assess IH-mediated sympathetic excitation in modulating pulmonary vasculature tone, particularly acute hypoxia vasoconstrictor response (HPV), and the central beta-adrenergic signaling pathway for facilitating the increase in SNA. Sprague-Dawley rats were exposed to IH (cycle of 4 % O-2 for 90 s/air for 90 s) for 8 h/day for 6 weeks. Subsequently, rats were anesthetized and either pulmonary SNA was recorded (electrophysiology), or the pulmonary vasculature was visualized using microangiography. Pulmonary sympathetic and vascular responses to acute hypoxia were assessed before and after central beta(1)-adrenergic receptor blockade (Metoprolol, 200 nmol i.c.v.). Chronic IH increased baseline SNA (110 % increase), and exacerbated the sympathetic response to acute hypoxia. Moreover, the magnitude of HPV in IH rats was blunted compared to control rats (e.g., 10 and 20 % vasoconstriction, respectively). In only the IH rats, beta(1)-receptor blockade with metoprolol attenuated the hypoxia-induced increase in pSNA and exacerbated the magnitude of acute HPV, so that both sympathetic and HPV responses were similar to that of control rats. Interestingly, the expression of beta(1)-receptors within the brainstem was similar between both control and IH rats. These results suggest that the centrally mediated increase in SNA following IH acts to blunt the local vasoconstrictor effect of acute hypoxia, which reflects an inherent difference between vasodilator and vasoconstrictor actions of SNA in pulmonary and systemic circulations.

DOI： 10.1007/s00395-014-0432-y

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：INFORMA HEALTHCARE  

DOI： 10.3109/15563650.2014.923906

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimCalpain activation has a putative role in ischaemia-reperfusion injury of cardiomyocytes. This study clarified the in vivo contribution of calpain to disruption of cardiomyocyte sarcolemma during ischaemia and after reperfusion in anaesthetized rats.
MethodsUsing a microdialysis technique in the hearts of anaesthetized rats, we investigated the effects of the calpain inhibitors on myocardial interstitial myoglobin level in the ischaemic region during coronary occlusion and after reperfusion. The calpain inhibitors were administered locally via a dialysis probe. Two durations of coronary occlusion were tested.
ResultsThirty-minute coronary occlusion: dialysate myoglobin concentration increased markedly from 38546ngmL(-1) at baseline to 3701 +/- 527ngmL(-1) at 20-30min of occlusion. After reperfusion, dialysate myoglobin concentration further increased, reaching a peak (12296 +/- 1564ngmL(-1)) at 10-20min post-reperfusion and then declined gradually. The calpain inhibitors, MDL-28170 and SNJ-1945 did not change dialysate myoglobin concentration during occlusion but attenuated the increase after reperfusion to 6826 +/- 1227 and 8130 +/- 938ngmL(-1) at 10-20min post-reperfusion (P&lt;0.05), respectively. Ninety-minute coronary occlusion: dialysate myoglobin concentration increased from 516 +/- 33ngmL(-1) at baseline to 5463 +/- 387ngmL(-1) at 80-90min after occlusion. After reperfusion, there was no significant increase in dialysate myoglobin concentration. MDL-28170 did not affect dialysate myoglobin concentration during occlusion or after reperfusion.
ConclusionCalpain contributes to sarcolemmal disruption immediately after reperfusion following 30-min coronary occlusion, but has little effects during ischaemia and after reperfusion in 90-min coronary occlusion.

DOI： 10.1111/apha.12205

Web of Science

PubMed

researchmap

記述言語：英語  

DOI： 10.1111/apha.12204

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The effects of muscle contractions on the profile of postcontraction resting intracellular Ca2+ ([Ca2+]i) accumulation in Type 1 diabetes are unclear. We tested the hypothesis that, following repeated bouts of muscle contractions, the rise in resting [Ca2+]ievident in healthy rats would be increased in diabetic rats and that these changes would be associated with a decreased cytoplasmic Ca2+-buffering capacity. Adult male Wistar rats were divided randomly into diabetic (DIA
streptozotocin, ip) and healthy control (CONT) groups. Four weeks later, animals were anesthetized and spinotrapezius muscle contractions (10 sets of 50 contractions) were elicited by electrical stimulation (100 Hz). Ca2+ imaging was achieved using Fura-2 AM in the spinotrapezius muscle in vivo (i.e., circulation intact). The ratio (340/380 nm) was determined from fluorescence images following each set of contractions for estimation of [Ca2+]i. Also, muscle Ca2+ buffering was studied in individual myocytes microinjected with 2 mM Ca2+ solution. After muscle contractions, resting [Ca2+]i in DIA increased earlier and more rapidly than in CONT (P &lt
0.05 vs. precontraction). Peak [Ca2+]i in response to the Ca2+ injection was significantly higher in CONT (25.8 ± 6.0% above baseline) than DIA (10.2 ± 1.1% above baseline). Subsequently, CONT [Ca2+]i decreased rapidly (&lt
15 s) to plateau 9-10% above baseline, whereas DIA remained elevated throughout the 60-s measurement window. No differences in SERCA1 and SERCA2 (Ca2+ uptake) protein levels were evident between CONT and DIA, whereas ryanodine receptor (Ca2+ release) protein level and mitochondrial oxidative enzyme activity (succinate dehydrogenase) were decreased in DIA (P &lt
0.05). In conclusion, diabetes impairs resting [Ca2+]i homeostasis following muscle contractions. Markedly different responses to Ca2+ injection in DIA vs. CONT suggest fundamentally deranged Ca2+ handling. © 2013 the American Physiological Society.

DOI： 10.1152/ajpregu.00023.2013

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Blockade of the serotonin reuptake transporter (5-HTT), using fluoxetine, has been identified as a potential therapeutic target for preventing and, importantly, reversing pulmonary hypertension (PH). This study utilized synchrotron radiation microangiography to determine whether fluoxetine could prevent or reverse endothelial dysfunction and vessel rarefaction, which underpin PH. PH was induced by a single injection of monocrotaline (MCT; 60 mg kg(-1)). Following MCT administration, rats received daily injections of either saline or fluoxetine (MCT + Fluox; 10 mg kg(-1)) for three weeks. A third group of rats also received the fluoxetine regime, but only three weeks after MCT (MCT + Fluox(Delay)). Control rats received daily injections of saline. Pulmonary microangiography was performed to assess vessel branching density and visualize dynamic changes in vessel diameter following (i) acute fluoxetine or (ii) acetylcholine, sodium nitroprusside, BQ-123 (ET-1(A) receptor blocker) and L-NAME (NOS inhibitor). Monocrotaline induced PH that was inevitably terminal. 'Delayed' treatment of fluoxetine (MCT + Fluox(Delay)) was unable to reverse the progression of PH. Early fluoxetine treatment pre-PH (i.e. MCT + Fluox) attenuated but did not completely prevent vascular remodeling, vessel rarefaction and an increase in pulmonary pressure, and it did not prevent pulmonary endothelial dysfunction. Interestingly, fluoxetine treatment did counter-intuitively prevent the onset of right ventricular hypertrophy. Using synchrotron radiation microangiography, selective blockade of the serotonin reuptake transporter alone is highlighted as not being sufficient to prevent pulmonary endothelial dysfunction, which is the primary instigator for the inevitable onset of vascular remodeling and vessel rarefaction. Accordingly, potential therapeutic strategies should aim to target multiple pathways to ensure an optimal outcome.

DOI： 10.1107/S0909049513021213

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Objectives: Activation of RhoA/Rho-kinase (ROCK) is increasingly implicated in acute vasospasm and chronic vasoconstriction in major organ systems. Therefore we aimed to ascertain whether an increase in ROCK activity plays a role in the deterioration of coronary vascular function in early stage diabetes.
Methods: Synchrotron radiation microangiography was used to determine in vivo coronary responses in diabetic (3 weeks post streptozotocin 65 mg/kg ip) and vehicle treated male Sprague-Dawley rats (n = 8 and 6). Changes in vessel number and calibre during vasodilator stimulation before and after blockade of nitric oxide synthase and cyclooxygenase were compared between rats. Acute responses to ROCK inhibitor, fasudil (10 mg/kg iv) was evaluated. Further, perivascular and myocardial fibrosis, arterial intimal thickening were assessed by histology, and capillary density, nitrotyrosine and ROCK1/2 expressions were evaluated by immunohistochemical staining.
Results: Diabetic rats had significantly elevated plasma glucose (P &lt; 0.001 vs control), but did not differ in fibrotic scores, media to lumen ratio, capillary density or baseline visible vessel number or calibre. Responses to acetylcholine and sodium nitroprusside stimulation were similar between groups. However, in comparison to control rats the diabetic rats showed more segmental constrictions during blockade, which were not completely alleviated by acetylcholine, but were alleviated by fasudil. Further, second order vessel branches in diabetic rats were significantly more dilated relative to baseline (37% vs 12% increase, P &lt; 0.05) after fasudil treatment compared to control rats, while visible vessel number increased in both groups. ROCK2 expression was borderline greater in diabetic rat hearts (P &lt; 0.053).
Conclusions: We found that ahead of the reported decline in coronary endothelial vasodilator function in diabetic rats there was moderate elevation in ROCK expression, more widespread segmental constriction when nitric oxide and prostacyclin production were inhibited and notably, increased calibre in second and third order small arteries-arterioles following ROCK inhibition. Based on nitrotyrosine staining oxidative stress was not significantly elevated in early diabetic rats. We conclude that tonic ROCK mediated vasoconstriction contributes to coronary vasomotor tone in early diabetes.

DOI： 10.1186/1475-2840-12-111

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Objectives: Atherosclerotic lesions of the coronary arteries are the pathological basis for myocardial infarction and ischemic cardiomyopathy. Progression of heart failure after myocardial infarction is associated with cardiac remodeling, which has been studied by means of coronary ligation in mice. However, this ligation model requires excellent techniques. Recently, a new murine model, HypoE mouse was reported to exhibit atherogenic Paigen diet-induced coronary atherosclerosis and myocardial infarction; however, the HypoE mice died too early to make possible investigation of cardiac remodeling. Therefore, we aimed to modify the HypoE mouse model to establish a novel model for ischemic cardiomyopathy caused by atherosclerotic lesions, which the ligation model does not exhibit.
Methods and Results: In our study, the sustained Paigen diet for the HypoE mice was shortened to 7 or 10 days, allowing the mice to survive longer. The 7-day Paigen diet intervention starting when the mice were 8 weeks old was adequate to permit the mice to survive myocardial infarction. Our murine model, called the "modified HypoE mouse", was maintained until 8 weeks, with a median survival period of 36 days, after the dietary intervention (male, n = 222). Echocardiography demonstrated that the fractional shortening 2 weeks after the Paigen diet (n = 14) significantly decreased compared with that just before the Paigen diet (n = 6) (31.4 +/- 11.9% vs. 54.4 +/- 2.6%, respectively, P&lt;0.01). Coronary angiography revealed multiple diffuse lesions. Cardiac remodeling and fibrosis were identified by serial analyses of cardiac morphological features and mRNA expression levels in tissue factors such as MMP-2, MMP-9, TIMP-1, collagen-1, and TGF-beta.
Conclusion: Modified HypoE mice are a suitable model for ischemic cardiomyopathy with multiple diffuse lesions and may be considered as a novel and convenient model for investigations of cardiac remodeling on a highly atherogenic background.

DOI： 10.1371/journal.pone.0070755

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized lowdensity lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions
however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH. © 2013 the American Physiological Society.

DOI： 10.1152/ajpheart.00169.2012

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We applied a microdialysis technique to the left ventricular myocardium of anesthetized mice and tried to monitor acetylcholine (ACh) release from cardiac vagal nerves. Transection of bilateral cervical vagal nerves decreased dialysate ACh concentration. Electrical stimulation of the left cervical vagal nerve increased dialysate ACh concentration in proportion to the frequency of stimulation. Intravenous administration of hexamethonium, prevented the increase in dialysate ACh concentration during vagal nerve stimulation, indicating that ACh in the dialysate primarily reflects ACh released from post-ganglionic cardiac vagal nerves. Microdialysis permits monitoring of ACh release from post-ganglionic cardiac vagal nerves that are most likely to be innervating the left ventricle in mice. (C) 2013 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2013.02.014

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Synchrotron radiation microangiography is a powerful tool for assessing adverse changes in pulmonary vessel density associated with primary pulmonary hypertension (PH). Congestive heart failure (CHF) leads to a 'secondary' onset of PH, yet it is unknown whether secondary PH is also associated with reduced vessel density. This study utilized synchrotron radiation to assess both pulmonary vessel density and endothelial function in a Dahl rat model of CHF with secondary PH. High salt-fed Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were anesthetized and microangiography was performed to assess the pulmonary vessel density and vascular responses to (i) sodium nitroprusside (5.0 mu g kg(-1) min(-1)), (ii) acetylcholine (3.0 mu g kg(-1) min(-1)) and (iii) ET-1(A) receptor blockade, BQ-123 (1 mg kg(-1)). Dahl-S rats developed CHF and secondary PH as evident by endothelial dysfunction, impaired vasodilatory responses to acetylcholine, enhanced vasodilatory responses to BQ-123 and extensive pulmonary vascular remodeling. Consequently, the pulmonary vessel density was adversely reduced. Interestingly, the etiology of secondary PH manifests with structural and functional changes that are comparable with that previously reported for primary PH. One important discrepancy, however, is that ET-1 modulation of pulmonary vessels is most striking in vessels with a diameter range of 100-200 mu m in secondary PH, in contrast to a range of 200-300 mm in primary PH. Such discrepancies should be considered in future studies investigating primary and secondary forms of PH.

DOI： 10.1107/S0909049513007413

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Diabetes is independently associated with a specific cardiomyopathy, characterized by impaired cardiac muscle relaxation and force development. Using synchrotron radiation small-angle x-ray scattering, this study investigated in the in situ heart and in real-time whether changes in cross-bridge disposition and myosin interfilament spacing underlie the early development of diabetic cardiomyopathy. Experiments were conducted using anesthetized Sprague-Dawley rats 3 weeks after treatment with either vehicle (control) or streptozotocin (diabetic). Diffraction patterns were recorded during baseline and dobutamine infusions simultaneous with ventricular pressure-volumetry. From these diffraction patterns myosin mass transfer to actin filaments was assessed as the change in intensity ratio (I-1,I-0/I-1,I-1). In diabetic hearts cross-bridge disposition was most notably abnormal in the diastolic phase (p &lt; 0.05) and to a lesser extent the systolic phase (p &lt; 0.05). In diabetic rats only, there was a transmural gradient of contractile depression. Elevated diabetic end-diastolic intensity ratios were correlated with the suppression of diastolic function (p &lt; 0.05). Furthermore, the expected increase in myosin head transfer by dobutamine was significantly blunted in diabetic animals (p &lt; 0.05). Interfilament spacing did not differ between groups. We reveal that impaired cross-bridge disposition and radial transfer may thus underlie the early decline in ventricular function observed in diabetic cardiomyopathy.

DOI： 10.1016/j.bpj.2013.01.037

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB-associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H2) would provide systemic anti-inflammatory and anti-apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H2 on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60min; and the CPB+H2 group in which H2 was given via an oxygenator during CPB for 60min. We collected blood samples before, 20min, and 60min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor-, interleukin-6, and interleukin-10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet-to-dry weight (W/D) ratio of the left lung 60min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20min after the CPB initiation and further increased 60min after the CPB initiation as compared with the SHAM group. In the CPB+H2 group, however, such increases were significantly suppressed at 60min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB+H2 group. We suggest that H2 insufflation is a possible new potential therapy for counteracting CPB-induced systemic inflammation.

DOI： 10.1111/j.1525-1594.2012.01535.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim Although deleterious effects of serotonin (5-HT) have been demonstrated during myocardial ischaemia-reperfusion, little information is available on myocardial interstitial 5-HT kinetics. This study evaluated the contribution of 5-HT reuptake and degradation to myocardial interstitial 5-HT levels during ischaemia-reperfusion. Methods Using microdialysis technique in anaesthetized rabbits, we monitored myocardial interstitial 5-HT levels in the ischaemic region during ischaemia (30 min) followed by reperfusion (60 min) and investigated the effects of local infusion of fluoxetine, a 5-HT uptake inhibitor, and/or pargyline, a monoamine oxidase inhibitor. Results In vehicle control, dialysate 5-HT concentration increased gradually from 16 +/- 3 at baseline to 85 +/- 18 nm during 2030 min of ischaemia. Dialysate 5-HT concentration further increased to 236 +/- 47 nm at 010 min of reperfusion and then began to decline. Averaged 5-HT concentration was 61 +/- 11 during ischaemia and 113 +/- 13 nm during reperfusion. Fluoxetine elevated dialysate 5-HT level at baseline and at 1030 min of reperfusion; it increased averaged dialysate 5-HT concentration by approx. 304% during reperfusion compared to control. Pargyline elevated averaged dialysate 5-HT concentration during ischaemia by approx. 243% and that during reperfusion by approx. 250% compared to control. The changes in dialysate 5-HT concentration by fluoxetine + pargyline were similar to those of fluoxetine alone. Conclusion The 5-HT reuptake function plays an important role in the clearance of myocardial interstitial 5-HT during reperfusion. When 5-HT reuptake function is intact, degradation of 5-HT by monoamine oxidase contributes to reduce myocardial interstitial 5-HT level throughout ischaemia-reperfusion.

DOI： 10.1111/j.1748-1716.2012.02461.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Japanese Society of Physical Fitness and Sports Medicine  

Contraction-induced compromise of muscle function and, in the extreme, muscle damage has been linked to loss of Ca²⁺ homeostasis and resultant sustained elevation of intracellular Ca²⁺ ([Ca²⁺]_i). Against a background of in vitro approaches, a novel in vivo model permits investigation of the impact of different contraction types (e.g., isometric, ISO; eccentric, ECC) on [Ca²⁺]_i accumulation profiles. [Ca²⁺]_i elevation of ECC-contracted muscle is more rapid and greater in magnitude compared to ISO. Stretch-activated channels (SAC) are responsible, in large part, for this ECC contractions-induced [Ca²⁺]_i elevation. Transient Ca²⁺ accumulation in the cytosol incurs loss of force production, whereas continuous high levels of [Ca²⁺]_i, especially following ECC contractions, lead to muscle damage, including disrupted sarcomeres and membranes, and proceed, subsequently, to muscle regeneration via apoptosis and necrosis.

DOI： 10.7600/jpfsm.1.505

CiNii Books

researchmap

その他リンク： https://jlc.jst.go.jp/DN/JALC/10010182054?from=CiNii

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective-In diabetes, long-term micro-and macrovascular damage often underlies the functional decline in the cardiovascular system. However, it remains unclear whether early-stage diabetes is associated with in vivo functional impairment in the coronary microvasculature. Synchrotron imaging allows us to detect and quantify regional differences in resistance microvessel caliber in vivo, even under conditions of high heart rate.
Methods and Results-Synchrotron cine-angiograms of the coronary vasculature were recorded using anesthetized Sprague-Dawley rats 3 weeks after treatment with vehicle or streptozotocin (diabetic). In the early diabetic state, in the presence of nitric oxide and prostacyclin, vessel diameters were smaller (P &lt; 0.01) and endothelium-dependent vessel recruitment was already depressed (P &lt; 0.05). Endothelium-dependent and -independent vasodilatory responses in individual coronary vessels were not different in vivo. Inhibition of NO and PGI(2) production in diabetes uncovered early localized impairment in dilation. Diabetic animals displayed focal stenoses and segmental constrictions during nitric oxide synthase/cyclooxygenase blockade, which persisted during acetylcholine infusion (P &lt; 0.05), and a strong trend toward loss of visible microvessels.
Conclusion-Synchrotron imaging provides a novel method to investigate coronary microvascular function in vivo at all levels of the arterial tree. Furthermore, we have shown that early-stage diabetes is associated with localized coronary microvascular endothelial dysfunction. (Arterioscler Thromb Vasc Biol. 2012; 32: 370-377.)

DOI： 10.1161/ATVBAHA.111.237172

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Ghrelin has cardioprotective properties and, recently, has been shown to improve endothelial function and reduce endothelin-1 (ET-1)-mediated vasoconstriction in peripheral vascular disease. Recently, we reported that ghrelin attenuates pulmonary hypertension (PH) caused by chronic hypoxia (CH), which we hypothesized in this study may be via suppression of the ET-1 pathway. We also aimed to determine whether ghrelin&apos;s ability to prevent alterations of the ET-1 pathway also prevented adverse changes in pulmonary blood flow distribution associated with PH. Sprague-Dawley rats were exposed to CH (10% O(2) for 2 weeks) with daily subcutaneous injections of ghrelin (150 mu g/kg) or saline. Utilizing synchrotron radiation microangiography, we assessed pulmonary vessel branching structure, which is indicative of blood flow distribution, and dynamic changes in vascular responsiveness to (1) ET-1 (1 nmol/kg), (2) the ET-1(A) receptor antagonist, BQ-123 (1 mg/kg), and (3) ACh (3.0 mu g kg(-1) min(-1)). CH impaired blood flow distribution throughout the lung. However, this vessel "rarefaction" was attenuated in ghrelin-treated CH-rats. Moreover, ghrelin (1) reduced the magnitude of endothelial dysfunction, (2) prevented an increase in ET-1-mediated vasoconstriction, and (3) reduced pulmonary vascular remodeling and right ventricular hypertrophy-all adverse consequences associated with CH. These results highlight the beneficial effects of ghrelin for maintaining optimal lung perfusion in the face of a hypoxic insult. Further research is now required to establish whether ghrelin is also an effective therapy for restoring normal pulmonary hemodynamics in patients that already have established PH.

DOI： 10.1007/s00424-011-0992-8

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Sonobe T, Schwenke DO, Pearson JT, Yoshimoto M, Fujii Y, Umetani K, Shirai M. Imaging of the closed-chest mouse pulmonary circulation using synchrotron radiation microangiography. J Appl Physiol 111: 75-80, 2011. First published April 28, 2011; doi:10.1152/japplphysiol.00205.2011.-Structural and functional changes of pulmonary circulation related to pathophysiology of pulmonary arterial hypertension (PAH) remain to be fully elucidated. Angiographic visualization in in vivo animals provided a powerful tool for assessing the major indexes associated with the pathogenesis of PAH. In this study, we have exploited the full potential of synchrotron radiation (SR) microangiography to show the ability to visualize pulmonary hemodynamics in a closed-chest mouse. Male adult mice were anesthetized and cannulated with a customized 24-gauge catheter into the right ventricle via the jugular vein for administering iodine contrast agent. The microangiography was performed on the left lung. We measured dynamic changes in vessel diameter in response to acetylcholine (ACh) and acute exposure to hypoxic gas (10% O(2)). Moreover, the pulmonary transit time was estimated by the time of contrast agent circulating. We were able to visualize the pulmonary arteries from the left pulmonary artery (LPA) to the third generation of branching (inner diameter &lt; 100 mu m). ACh and acute hypoxia induced vascular responses chiefly in the second and third branching vessels rather than the LPA and the first branching vessels. The transit time was only 0.83 s. These results demonstrate the effectiveness of SR for visualizing the pulmonary circulation in a closed-chest mouse. Future studies using SR microangiography on specific gene-targeted knockout and transgenic mice will provide new insights into the pathophysiology of pulmonary dysfunction and functional adaptation to survive in hypoxic condition.

DOI： 10.1152/japplphysiol.00205.2011

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Although central ghrelin has cardioprotective effect through inhibiting sympathetic nerve activity, the effects of central ghrelin on cardiac vagal nerve remain unknown. We investigated the effects of centrally administered ghrelin on cardiac autonomic nerve activities using microdialysis technique. A microdialysis probe was implanted in the right atrial wall adjacent to the sinoatrial node of an anesthetized rabbit and was perfused with Ringer's solution containing a cholinesterase inhibitor, eserine. After injection of ghrelin (1 nmol) into the right lateral cerebral ventricle, norepinephrine (NE) and acetylcholine (ACh) concentrations in the dialysate samples were measured as indices of NE and ACh release from nerve endings to the sinoatrial node using high-performance liquid chromatography. Heart rate was 270 +/- 4 bpm at baseline and decreased gradually after ghrelin injection to 234 +/- 9 bpm (P&lt;0.01) at 60-80 min, followed by gradual recovery. Dialysate ACh concentration was 5.5 +/- 0.8 nM at baseline and increased gradually after ghrelin injection to 8.8 +/- 1.2 nM (P&lt;0.01) at 60-80 min: the concentration started to decrease gradually from 100 to 120 min after injection reaching 5.6 +/- 0.8 nM at 160-180 min. Central ghrelin did not change mean arterial pressure or dialysate NE concentration. The elevated dialysate ACh concentration declined rapidly after transection of cervical vagal nerves. These results indicate that centrally administered ghrelin activates cardiac vagal nerve. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2011.04.001

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

An X-ray stereo imaging system with synchrotron radiation was developed at BL20B2, SPring-8. A portion of a wide X-ray beam was Bragg-reflected by a silicon crystal to produce an X-ray beam which intersects with the direct X-ray beam. Samples were placed at the intersection point of the two beam paths. X-ray stereo images were recorded simultaneously by a detector with a large field of view placed close to the sample. A three-dimensional wire-frame model of a sample was created from the depth information that was obtained from the lateral positions in the stereo image. X-ray stereo angiography of a mouse femoral region was performed as a demonstration of real-time stereo imaging. Three-dimensional arrangements of the femur and blood vessels were obtained.

DOI： 10.1107/S0909049511017547

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12576-011-0134-2

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Schwenke DO, Pearson JT, Sonobe T, Ishibashi-Ueda H, Shimouchi A, Kangawa K, Umetani K, Shirai M. Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension. J Appl Physiol 110: 901-908, 2011. First published January 6, 2011; doi:10.1152/japplphysiol.01318.2010.-Rho-kinase-mediated vasoconstriction and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). However, their contribution to the adverse changes in pulmonary blood flow distribution associated with PAH has not been addressed. This study utilizes synchrotron radiation microangiography to assess the specific role, and contribution of, Rho-kinase-mediated vasoconstriction and endothelial dysfunction in PAH. Male adult Sprague-Dawley rats were injected with saline (Cont-rats) or monocrotaline (MCT-rats) 3 wk before microangiography was performed on the left lung. We assessed dynamic changes in vessel internal diameter (ID) in response to 1) the Rho-kinase inhibitor fasudil (10 mg/kg iv); or 2) ACh (3 mu g.kg(-1).min(-1)), sodium nitroprusside (SNP, 5 mu g.kg(-1).min(-1)), and N-omega-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg iv). We observed that MCT-rats had fewer vessels of the microcirculation compared with Cont-rats. The fundamental result of this study is that fasudil improved pulmonary blood flow distribution and reduced pulmonary pressure in PAH rats, not only by dilating already-perfused vessels (ID &gt; 100 mu m), but also by restoring blood flow to vessels that had previously been constricted closed (ID &lt; 100 mu m). Endothelium-dependent vasodilation was impaired in MCT-rats primarily in vessels with an ID &lt; 200 mu m. Moreover the vasoconstrictor response to L-NAME was accentuated in MCT-rats, but only in the 200- to 300-mu m vessels. These results highlight the importance of Rho-kinase-mediated control and endothelial control of pulmonary vascular tone in PAH. Indeed, an effective therapeutic strategy for treating PAH should target both the smooth muscle Rho-kinase and endothelial pathways.

DOI： 10.1152/japplphysiol.01318.2010

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Rationale: Grb2-associated binder (Gab) docking proteins, consisting of Gab1, Gab2, and Gab3, have crucial roles in growth factor-dependent signaling. Various proangiogenic growth factors regulate angiogenesis and endothelial function. However, the roles of Gab proteins in angiogenesis remain elusive.
Objective: To elucidate the role of Gab proteins in postnatal angiogenesis.
Methods and Results: Endothelium-specific Gab1 knockout (Gab1ECKO) mice were viable and showed no obvious defects in vascular development. Therefore, we analyzed a hindlimb ischemia (HLI) model of control, Gab1ECKO, or conventional Gab2 knockout (Gab2KO) mice. Intriguingly, impaired blood flow recovery and necrosis in the operated limb was observed in all of Gab1ECKO, but not in control or Gab2KO mice. Among several proangiogenic growth factors, hepatocyte growth factor (HGF) induced the most prominent tyrosine phosphorylation of Gab1 and subsequent complex formation of Gab1 with SHP2 (Src homology-2-containing protein tyrosine phosphatase 2) and phosphatidylinositol 3-kinase subunit p85 in human endothelial cells (ECs). Gab1-SHP2 complex was required for HGF-induced migration and proliferation of ECs via extracellular signal-regulated kinase (ERK) 1/2 pathway and for HGF-induced stabilization of ECs via ERK5. In contrast, Gab1-p85 complex regulated activation of AKT and contributed partially to migration of ECs after HGF stimulation. Microarray analysis demonstrated that HGF upregulated angiogenesis-related genes such as KLF2 (Kruppel-like factor 2) and Egr1 (early growth response 1) via Gab1-SHP2 complex in human ECs. In Gab1ECKO mice, gene transfer of vascular endothelial growth factor, but not HGF, improved blood flow recovery and ameliorated limb necrosis after HLI.
Conclusion: Gab1 is essential for postnatal angiogenesis after ischemia via HGF/c-Met signaling. (Circ Res. 2011; 108: 664-675.)

DOI： 10.1161/CIRCRESAHA.110.232223

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Sonobe T, Inagaki T, Sudo M, Poole DC, Kano Y. Sex differences in intracellular Ca2+ accumulation following eccentric contractions of rat skeletal muscle in vivo. Am J Physiol Regul Integr Comp Physiol 299: R1006-R1012, 2010. First published July 14, 2010; doi:10.1152/ajpregu.00623.2009.-It is commonly believed that estrogen and sex influences play significant effects in skeletal muscle damage following eccentric exercise. The mechanistic bases for this sex-specific phenomenon remain to be resolved. The muscle damage has been linked to loss of Ca2+ homeostasis and resultant intramyocyte Ca2+ ([Ca2+](i)) accumulation; therefore, we tested the hypothesis that the greater eccentric exercise-induced muscle damage in males would be associated with more pronounced [Ca2+](i) accumulation. The intact spinotrapezius muscle of adult Wistar rats [male, female, and ovariectomized (OVX)-to investigate the effects of estrogen] was exteriorized. Tetanic eccentric contractions (100 Hz, 700-ms duration, 20 contractions/min for a total of 10 sets of 50 contractions) were elicited by electrical stimulation during synchronized muscle stretch of 10% resting muscle length. The fluorescence ratio (F340/F-380 nm) was determined from images captured following each set of contractions, and fura-2 AM was used to estimate [Ca2+](i) and changes thereof. Following eccentric contractions, [Ca2+](i) increased significantly in male (42.8 +/- 5.3%, P &lt; 0.01) but not in female (9.4 +/- 3.5%) rats. OVX evidenced an intermediate response (17.0 +/- 1.2%) that remained significantly reduced compared with males. These results demonstrate that females maintain [Ca2+](i) homeostasis following novel eccentric contractions, whereas males do not, which is consistent with a role for elevated [Ca2+](i) in eccentric exercise-induced muscle damage. The presence of normal estrogen levels is not obligatory for the difference between the sexes.

DOI： 10.1152/ajpregu.00623.2009

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG BERLIN  

Using a fatiguing stimulation protocol designed specifically to enhance sympathetically-mediated vasoconstrictor tone, we explored the temporal profile of the evoked vasoconstrictor response, evaluated the presence of sympatholysis, and assessed the role of c alpha 1-adrenergic receptor-mediated vasoconstriction on muscle performance. Spinotrapezius muscles of Wistar rats were exteriorized and stimulated tetanically (100 Hz, 4-7 V, stimulus duration 700 ms) every 3 s for 2.5 min under control and prazosin (1 mu M) superfused conditions. The extent and time course of diameter changes in arterioles (2A) and venules (2V) were determined after each of 10 discrete sets of muscle stimulation at 5-min intervals. A significant decrease of luminal diameter was observed in arterioles after tetanic contractions at 8-10 sets (8 sets: -34.4%, 9 sets: -39.4%, 10 sets: -38.6% vs pre-contraction at each set, p &lt; 0.01). Prazosin significantly reduced but did not abolish the contraction-induced vasoconstriction. In both conditions, there was no reduction of venules diameter observed. Tetanic contractions force at the final 10th set was significantly decreased to 29.3 +/- 11.9% from pre-fatigue conditions, while tetanic contractions with prazosin force production was maintained at 70.4 +/- 14.2% at the 10th set. We conclude that in sequential bouts of contractions there was a progressively greater degree of arteriolar (but not venular) vasoconstriction which was attenuated substantially by prazosin.

DOI： 10.1007/978-1-4419-1241-1_44

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Although the accumulation of intracellular calcium ions ([Ca2+](i)) is associated with muscle damage, little is known regarding the temporal profile of muscle [Ca2+](i) under in vivo conditions, and, specifically, the effects of different contraction types [e. g., isometric (ISO); eccentric (ECC)] on [Ca2+](i) remain to be determined. The following hypotheses were tested. 1) For 90 min at rest, an in vivo vs. in vitro preparation would better maintain initial [Ca2+](i). 2) Compared with ISO, ECC contractions (50 contractions, 10 sets, 5-min interval) would lead to a greater increase of [Ca2+](i). 3) Elevated [Ca2+](i) during ECC would be reduced or prevented by the stretch-activated ion channel blockers streptomycin and gadolinium (Gd3+). Spinotrapezius muscles of Wistar rats were exteriorized (in vivo) or excised (in vitro). [Ca2+](i) was evaluated by loading the muscle with fura 2-AM using fluorescence imaging. [Ca2+](i) rose progressively beyond 40 min at rest under in vitro but not in vivo conditions during the 90-min protocol. In vivo [Ca2+](i) increased more rapidly during ECC (first set) than ISO (fifth set) (P &lt; 0.05 vs. precontraction values). The peak level of [Ca2+](i) was increased by 21.5% (ISO) and 42.8% (ECC) after 10 sets (both P &lt; 0.01). Streptomycin and Gd3+ abolished the majority of [Ca2+](i) increase during ECC (69 and 86% reduction, respectively; P &lt; 0.01 from peak [Ca2+](i) of ECC). In conclusion, in vivo quantitative analyses demonstrated that ECC contractions elevate [Ca2+](i) significantly more than ISO contractions and that stretch-activated channels may play a permissive role in this response.

DOI： 10.1152/ajpregu.00815.2007

Web of Science

PubMed

researchmap

出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/01.hjh.0000747312.60087.49

researchmap

記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：CELL PRESS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Web of Science

researchmap

記述言語：英語  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER JAPAN KK  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER JAPAN KK  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER JAPAN KK  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：(一社)日本体力医学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本体力医学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER TOKYO  

Web of Science

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本体力医学会  

CiNii Books

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本体力医学会  

CiNii Books

researchmap

記述言語：日本語   出版者・発行元：日本体力医学会  

CiNii Books

researchmap

記述言語：日本語   出版者・発行元：日本体力医学会  

CiNii Books

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本体力医学会  

CiNii Books

researchmap

記述言語：日本語   出版者・発行元：日本体力医学会  

CiNii Books

J-GLOBAL

researchmap