Y Matsumura

Osaka University of Pharmaceutical Sciences, Ōsaka, Ōsaka, Japan

Are you Y Matsumura?

Claim your profile

Publications (266)628.51 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The effects of hormone replacement therapy with estrogen on cardiovascular disease in postmenopausal women are still controversial. In the present study, we examined the effects of an endothelin (ET) receptor antagonist (ERA) and/or angiotensin receptor blocker (ARB) on neointimal formation following vascular injury in ovariectomized (OVX) female rats. Female rats were divided into intact female and OVX groups. The right carotid artery was subjected to balloon injury, and harvested 2 weeks later. In the intact female groups, treatment with ARB (L-158809; 1mg/kg/day) for two weeks after the injury significantly decreased neointimal formation, whereas treatment with the ERA (J-104132; 10mg/kg/day) did not affect neointimal formation. On the other hand, the ERA markedly decreased neointimal formation after the injury in the OVX groups; however, neointimal formation was not significantly improved by the ARB treatment. In addition, the combined treatment with 17β-estradiol (20μg/kg/day) or the ERA and ARB markedly suppressed neointimal formation after the balloon injury in the OVX groups, whereas no combinational effects were observed due to the combined treatment with 17β-estradiol and the ERA. These results suggest that ERAs have estrogen-like vasoprotective effects on neointimal formation following balloon injury in OVX rats. ERAs may be useful as an alternative therapy to prevent vascular disease in postmenopausal women.
    Life sciences 01/2014; · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the effects of oligomycin, an F1FO-ATPase inhibitor, on ischemic acute kidney injury in male and female rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 or 60 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal dysfunction and histological renal damage were observed 1 day after reperfusion in both male and female rats, although these renal injuries were more marked in male rats than in female rats. Intravenous bolus injection of oligomycin (0.5 mg/kg) 5 min before ischemia markedly attenuated the ischemia/reperfusion-induced renal injury in male rats. However, oligomycin did not show the protective effect in female rats subjected to ischemia/reperfusion-induced renal injury. Pre-ischemic treatment with oligomycin suppressed partly but significantly ischemia-induced renal ATP depletion only in male rats. These results indicate that oligomycin prevents the onset of ischemic acute kidney injury in male but not in female rats, and the effect is accompanied by suppression of the ATP depletion only in the male rat kidney during ischemia, thereby suggesting that the ATP hydrolysis pathway by mitochondrial F1FO-ATPase induces a sex difference in ischemic acute kidney injury.
    Journal of Pharmacological Sciences 10/2013; · 2.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sleep apnea (SA) causes not only sleep disturbances, but also neurocognitive impairments and/or psychoemotional disorders. Here, we studied the effects of intermittent hypoxia (IH) on forebrain Fos expression using obese diabetic db/db mice to explore the pathophysiological alterations in neural activities and the brain regions related to SA syndrome. Male db/db mice were exposed to IH stimuli (repetitive 6-min cycles of 1min with 5% oxygen followed by 5min with 21% oxygen) for 8hours (80 cycles) per day or normoxic condition (control group) for 14 days. Fos protein expression was immunohistochemically examined a day after the last IH exposure. Mapping analysis revealed a significant reduction of Fos expression by IH in limbic and paralimbic structures, including the cingulate and piriform cortices, the core part of the nucleus accumbens and most parts of the amygdala (i.e., the basolateral and basomedial amygdaloid nuclei, cortical amygdaloid area and medial amygdaloid nucleus). In the brain stem regions, Fos expression was region-specifically reduced in the ventral tegmental area while other regions including the striatum, thalamus and hypothalamus, were relatively resistant against IH. In addition, db/db mice exposed to IH showed a trend of sedative and/or depressive behavioral signs in the open field and forced swim tests. The present results illustrate that SA in the obese diabetic model causes neural suppression preferentially in the limbic and paralimbic regions, which may be related to the neuropsychological disturbances associated with SA.
    Neuroscience Research 10/2013; · 2.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Time-dependent changes in the renal sympathetic nerve activity (RSNA) in the progression of chronic kidney disease (CKD) have not been investigated, despite the fact that renal sympathetic nervous system is augmented in the condition of CKD. In the present study, we examined time-dependent changes in RSNA and renal venous norepinephrine concentrations for 12 weeks, using 5/6 nephrectomized CKD rats. Both RSNA and norepinephrine concentrations were increased during the early phase in the progression of CKD. Urinary protein excretion and systolic blood pressure (SBP) were gradually increased during 12 weeks after 5/6 nephrectomy. Treatment with γ-aminobutyric acid (GABA) or the combination of prazosin and propranolol in the early phase (0-4 weeks) after 5/6 nephrectomy significantly attenuated the increases in urinary protein excretion and SBP in 5/6 nephrectomized rats. On the other hand, the same treatment in the late phase (8-12 weeks) after 5/6 nephrectomy failed to suppress the proteinuria and increase in SBP. Treatment with hydralazine at hypotensive dose for 12 weeks also failed to affect the proteinuria in 5/6 nephrectomized CKD rats. In conclusion, the augmentation of renal sympathetic nervous system in early phase after 5/6 nephrectomy is closely related to the development of partial ablation-induced CKD in rats.
    Journal of cardiovascular pharmacology 09/2013; · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Enhancement of renal sympathetic nerve activity during renal ischemia and norepinephrine overflow from the kidney after reperfusion play important roles in the development of ischemic acute kidney injury. Recently, we have found that moxonidine, an α2/imidazoline Ι1-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the excitation of renal sympathetic nervous system after reperfusion. In the present study, to clarify the renoprotective mechanisms of moxonidine (360nmol/kg, i.v.) against ischemic acute kidney injury, we investigated the effect of intravenous (i.v.) and intracerebroventricular (i.c.v.) injection of efaroxan, an α2/ Ι1 receptor antagonist, on the moxonidine-exhibited actions. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. The suppressive effect of moxonidine on enhanced renal sympathetic nerve activity during renal ischemia was not observed in the rat treated with either i.v. (360nmol/kg) or i.c.v. (36nmol/kg) of efaroxan. Furthermore, i.v. injection of efaroxan eliminated the preventive effect of moxonidine on ischemia/reperfusion-induced kidney injury and norepinephrine overflow, and i.c.v. injection of efaroxan did not completely inhibit the moxonidine's effects. These results indicate that moxonidine prevents the ischemic kidney injury by sympathoinhibitory effect probably via α2/Ι1 receptors in central nervous system and by suppressing the norepinephrine overflow through α2/Ι1 receptors on sympathetic nerve endings.
    European journal of pharmacology 09/2013; · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have found that a series of brief renal ischemia and reperfusion (preconditioning), before the time of ischemia significantly attenuated the ischemia/reperfusion-induced acute kidney injury through endothelial nitric oxide synthase. In this study, we examined the effects of ischemic preconditioning on renal sympathetic nervous system and kidney function in ischemia/reperfusion-induced acute kidney injury with or without nitric oxide synthase inhibitor. Ischemia/reperfusion-induced acute kidney injury was made by clamping the left renal artery and vein for 45-min followed by reperfusion, 2 weeks after the contralateral nephrectomy. Ischemic preconditioning, consisting of three cycles of 2-min ischemia followed by 5-min reperfusion, was performed before the 45-min ischemia. Ischemic preconditioning suppressed the enhanced renal sympathetic nerve activity during ischemia and the elevated renal venous plasma norepinephrine level after reperfusion, and attenuated renal dysfunction and histological damage. The renoprotective effect of ischemic preconditioning was diminished by N(G)-nitro-L-arginine methyl ester (0.3mg/kg, i.v.), a nonselective nitric oxide synthase inhibitor, 5min before the start of ischemic preconditioning. Thus, ischemic preconditioning decreased renal sympathetic nerve activity and norepinephrine release probably through activating nitric oxide production, thereby improving ischemia/reperfusion-induced acute kidney injury.
    European journal of pharmacology 09/2013; · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to ischemic acute kidney injury has been shown to be higher in female rats than in male rats. We found that renal venous norepinephrine overflow after reperfusion played important roles in the development of ischemic acute kidney injury. In the present study, we investigated whether sex differences in the pathogenesis of ischemic acute kidney injury were derived from the renal sympathetic nervous system using male and female Sprague-Dawley rats. Ischemia/reperfusion-induced acute kidney injury was achieved by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was impaired after reperfusion in both male and female rats; however, renal dysfunction and histological damage were more severe in male rats than in female rats. Renal venous plasma norepinephrine levels after reperfusion were markedly elevated in male rats, but were not in female rats. These sex differences were eliminated by ovariectomy or treatment with tamoxifen, an estrogen receptor antagonist, in female rats. Furthermore, an intravenous injection of hexamethonium (25mg/kg), a ganglionic blocker, 5min before ischemia suppressed the elevation in renal venous plasma norepinephrine levels after reperfusion, and attenuated renal dysfunction and histological damage in male rats, and ovariectomized and tamoxifen-treated female rats, but not in intact females. Thus, the present findings confirmed sex differences in the pathogenesis of ischemic acute kidney injury, and showed that the attenuation of ischemia/reperfusion-induced acute kidney injury observed in intact female rats may be dependent on depressing the renal sympathetic nervous system with endogenous estrogen.
    European journal of pharmacology 07/2013; · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously reported that intermittent hypoxic stress, which is relevant to sleep apnea syndrome (SAS), increases oxidative stress and induces left ventricular (LV) remodeling. Celiprolol, a β1-selective adrenoreceptor blocker, is known to have not only an antihypertensive effect but also an antioxidant effect through releasing nitric oxide. The aim of this study was to examine the hypothesis that celiprolol might ameliorate the LV remodeling induced by intermittent hypoxia through its antioxidant effect. Male C57BL/6J mice (8 weeks old) were exposed to intermittent hypoxia (30 s of 5% oxygen followed by 30 s of 21% oxygen) for 8 h day(-1) during the daytime for 10 consecutive days or were maintained under normoxic conditions. Animals were treated with either celiprolol (100 mg kg(-1) day(-1) by gavage) or vehicle. Hypoxic stress caused fluctuations in blood pressure (BP), an increase in the mean cardiomyocyte diameter, perivascular fibrosis and a decrease in endothelial nitric oxide synthase (eNOS) expression. These changes were associated with increased levels of 4-hydroxy-2-nonenal protein, superoxide, tumor necrosis factor-α mRNA and brain natriuretic peptide mRNA in the LV myocardium. Celiprolol significantly suppressed BP fluctuation, restored eNOS expression and reduced oxidative stress and superoxide production, thus ameliorating hypoxia-induced LV remodeling in mice. These findings suggest that treatment with celiprolol might prevent cardiovascular events in borderline hypertensive patients with SAS.Hypertension Research advance online publication, 20 June 2013; doi:10.1038/hr.2013.60.
    Hypertension Research 06/2013; · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species and norepinephrine are known as physiological active substances which cause cell damage and cardiac dysfunction in myocardial ischemia/reperfusion injury. We investigated the role of reactive oxygen species, especially superoxide (O2(-)), in ischemia-induced norepinephrine overflow and cardiac dysfunction using superoxide scavengers tempol and tiron. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Tempol (10 and 100µM) and tiron (100 and 500µM) were perfused 15min before ischemia and during reperfusion. Cardiac levels of oxidative stress markers such as O2(-) and malondialdehyde were notably increased during ischemia and following reperfusion, which were suppressed by the administration of tempol or tiron. These agents significantly improved ischemia/reperfusion-induced cardiac dysfunction such as decreased left ventricular developed pressure and the maximum and minimum value of the first derivative of left ventricular pressure and increased left ventricular end-diastolic pressure. Furthermore, norepinephrine overflow in the coronary effluent after ischemia/reperfusion was significantly suppressed by the administration of each agent. These results suggest that endogenously increased O2(-) is involved in norepinephrine overflow and cardiac dysfunction after myocardial ischemia/reperfusion.
    European journal of pharmacology 04/2013; · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined the effects of angiotensin II AT(1)-receptor blockade with olmesartan on high fat (HF) diet-induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet-fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats. NS + HF diet-fed DSS rats also showed higher plasma levels of thiobarbituric acid-reactive substances, aortic superoxide production, and mRNA levels of p22(phox) and gp91(phox) in aortic tissues than NS diet-fed DSS rats. Furthermore, acetylcholine-induced vasorelaxation of aorta from NS + HF diet-fed DSS rats was significantly reduced. In NS + HF diet-fed DSS rats, treatment with olmesartan medoxomil (10 mg/kg per day, p.o.) and hydralazine (25 mg/kg per day, p.o.) similarly decreased blood pressure. However, in these animals, only olmesartan normalized plasma levels of thiobarbituric acid-reactive substances, vascular superoxide in aortic tissues, and acetylcholine-induced vasorelaxation. These data indicate that HF diet-induced hypertension is associated with vascular oxidative stress and endothelial dysfunction in NS diet-treated DSS rats. Inhibition of angiotensin II AT(1) receptors may elicit beneficial effects on HF-induced hypertension and vascular injury in subjects that have genetically enhanced sodium-sensitive blood pressure.
    Journal of Pharmacological Sciences 01/2013; · 2.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study was undertaken to examine the effect of acute treatment with 17β-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow and its possible mechanisms. Male rat hearts were perfused with the Langendorff method and subjected to 40min of global ischemia followed by 30min of reperfusion. Each drug was perfused from 15min before ischemia to 5min after reperfusion. During reperfusion, 17β-estradiol treatment showed significantly greater functional recovery of left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), and dP/dt(max). Excessive norepinephrine release in coronary effluent from the post-ischemic heart was notably suppressed by treatment with 17β-estradiol. These beneficial effects of 17β-estradiol were not observed in the presence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine and estrogen receptor antagonist ICI 182,780 ((7α, 17β)-7-[9-[(4,4,5,5,5pentafluoropentyl)Sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol), respectively. When NO(2)/NO(3) levels in coronary effluents after the onset of reperfusion were measured, reverse-correlation relationships between NO(2)/NO(3) production and ischemia/reperfusion-induced cardiac dysfunction, as well as norepinephrine overflow were observed. These findings suggest that 17β-estradiol exerts cardioprotective effects against ischemia/reperfusion-induced cardiac dysfunction, at least in part, by suppressing norepinephrine overflow, and that nitric oxide production via estrogen receptor activation plays a key role in this process.
    European journal of pharmacology 12/2012; · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis. Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ET(A)- and ET(B)-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ET(B)-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ET(A)- or nonselective ET(A)/ET(B)-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ET(B) receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ET(B) receptor, in CVD.
    Journal of Pharmacological Sciences 07/2012; 119(4):302-13. · 2.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study is to elucidate the relationship between sex difference and norepinephrine (NE) release in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Isolated male and female rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Compared with male hearts, I/R-induced cardiac dysfunction, such as decreased left ventricular developed pressure and dP/dtmax and increased left ventricular end diastolic pressure, was significantly attenuated in female hearts. An excessive NE overflow in the coronary effluent from the postischemic heart in females was much less than that in males. These sex differences were abolished by ovariectomy, but in vivo treatment with 17β-estradiol recovered it. This ameliorating effect of 17β-estradiol was not observed in the presence of nitric oxide (NO) synthase inhibitor N-nitro-L-arginine. When NOx (NO2/NO3) levels in the coronary effluent after onset of reperfusion were measured, reversed correlated relationships between NOx production and I/R-induced cardiac dysfunction, and NE overflow, were observed. These findings suggest that sex differences in the postischemic cardiac dysfunction are closely related to the NE overflow from the postischemic heart and that estrogen plays a key role in the cardioprotective effect against I/R injury in female rats, by suppressing NE release via the enhancement of NO production.
    Journal of cardiovascular pharmacology 05/2012; 60(3):269-75. · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been reported that endothelin-1 (ET-1) overproduction and reduced nitric oxide (NO) production are closely related to the progression of renal diseases. In the present study, we examined the interrelation between ET-1 and NO system using rats treated with the combination of deoxycorticosterone acetate (DOCA)-salt and a non selective NO synthase inhibitor N(ω)-nitro-l-arginine (NOARG). Rats were treated with DOCA-salt (15mg/kg, plus drinking water containing 1% NaCl) for two weeks, and then additional treatment of NOARG (0.6mg/ml in the drinking water) was performed for three days. Combined treatment of DOCA-salt and NOARG drastically developed the severe renal dysfunction and tissue injury. This treatment additionally enhanced renal ET-1 production compared to the rats treated with DOCA-salt alone, whereas a selective ET(A) receptor antagonist ABT-627 completely prevented renal dysfunction and tissue injury. On the other hand, combined treatment of DOCA-salt and NOARG induced the phosphorylation of inhibitory protein kappa B (IκB), followed by the activation of nuclear factor-kappa B (NF-κB) in the kidney. In addition, pyrrolidine-dithiocarbamate completely suppressed not only NF-κB activation but also renal dysfunction and ET-1 overproduction. These results suggest that NF-κB/ET-1/ET(A) receptor-mediated actions are responsible for the increased susceptibility to DOCA-salt induced renal injuries in the case of reduced NO production.
    Life sciences 04/2012; 91(13-14):644-50. · 2.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been reported that activation of the sympathetic nervous system and increase in plasma norepinephrine (NE) levels are observed in patients with pulmonary hypertension (PH). γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system and suppresses peripheral sympathetic neurotransmission. This study investigated whether chronic treatment with GABA prevents the development of monocrotaline (MCT)-induced PH. To elucidate the relationship between the development of PH and sympathetic nerve activity, hemodynamic parameters, cardiac functions, and plasma NE concentrations as well as cardiac endothelin-1 (ET-1) contents of MCT-induced PH rats were evaluated with or without GABA treatment. Rats were injected with MCT (60mg/kg) or saline subcutaneously and these rats were randomly divided into GABA (500mg/kg/day for 4weeks)- or vehicle-treated groups, respectively. KEY FINDING: MCT-treated rats had higher right ventricular systolic pressures, right ventricle-to-left ventricle plus septum weight ratios, pulmonary arterial medial thickening, and plasma NE levels than those of saline-injected rats. MCT-induced alternations were significantly attenuated by treatment with GABA. In MCT-induced PH rats with or without GABA treatment, plasma NE levels were positively correlated with right ventricular systolic pressure. Right ventricular endothelin-1 (ET-1) contents were increased by MCT injection, but these increments were not affected by treatment with GABA. These results suggest that plasma NE levels play an important role in the development of MCT-induced PH in rats and that GABA exerts a preventive effect against MCT-induced PH by suppressing the sympathetic nervous system but not the cardiac ET-1 system.
    Life sciences 04/2012; 91(13-14):693-8. · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiotensin type 1 receptor (AT1R) antagonist and endothelin type A receptor (ET(A)R) antagonist were compared as regards their effects on ischemia-induced exocytotic or carrier-mediated norepinephrine (NE) release from cardiac sympathetic nerve endings. According to the Langendorff technique, isolated rat hearts were subjected to 20-minute or 40-minute global ischemia followed by 30-minute reperfusion. Candesartan (selective AT1R antagonist) and ABT-627 (selective ET(A)R antagonist) were perfused, beginning 15 minutes before ischemia. Candesartan (10 and 100 nM) and ABT-627 (3 μM) suppressed excessive NE overflow (exocytotic release) in the coronary effluent from the heart exposed to 20-minute ischemia. In addition, these agents improved postischemic cardiac dysfunction. On the other hand, the beneficial effects of ABT-627 (1 and 3 μM) on NE overflow (carrier-mediated release) and cardiac dysfunction were also observed in 40-minute ischemia, whereas those were not improved by treatment with candesartan (10 and 100 nM and 1 μM). These findings suggest that both AT1R antagonist and ET(A)R antagonist have ability to inhibit the exocytotic NE release, but the carrier-mediated NE release induced by prolonged ischemia cannot be avoided by AT1R antagonist. Thus, ET(A)R antagonist may be more useful than AT1R antagonist in the clinical settings of ischemic heart disease.
    Journal of cardiovascular pharmacology 04/2012; 60(1):55-60. · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Enhanced renal sympathetic nerve activity during an ischemic period and renal venous norepinephrine overflow after reperfusion play important roles in the development of ischemic acute kidney injury. In this study, we examined the effect of 17β-estradiol on the renal sympathetic nervous system and kidney function in ischemia/reperfusion-induced acute kidney injury in anesthetized rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after a contralateral nephrectomy. Intravenous injection of 17β-estradiol (100 μg/kg) 15 min before reperfusion suppressed enhanced renal sympathetic nerve activity during renal ischemia, also suppressed renal venous norepinephrine overflow after reperfusion, and attenuated ischemia/reperfusion-induced renal dysfunction with histological damage. The above renoprotective effects of 17β-estradiol were reversed by pretreatment with tamoxifen (5 mg/kg), an estrogen receptor antagonist, or N(G)-nitro-L-arginine methyl ester (0.3 mg/kg), a non-selective nitric oxide synthase inhibitor. These results indicate that 17β-estradiol can suppress enhanced renal sympathetic nerve activity during renal ischemia, and its consequent effect on norepinephrine overflow from nerve endings, by nitric oxide production via estrogen receptors. These effects appear to contribute to renoprotection against ischemia/reperfusion-induced renal injury.
    European journal of pharmacology 03/2012; 683(1-3):270-5. · 2.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In protracted myocardial ischemia, sympathetic activation with carrier-mediated excessive norepinephrine (NE) release from its nerve endings due to reversal of NE transporter in an outward direction is a prominent cause of arrhythmias and cardiac dysfunction. Endothelin-1 (ET-1) and its receptors are intimately involved in the regulation of this carrier-mediated NE overflow in protracted myocardial ischemia. The ET-1 system is often complex, sometimes involving opposing actions depending on which receptor subtype is activated, which cells are affected, and whether stimuli are endogenously generated or exogenously applied. Therefore, a detailed understanding of the ET-1 system is important for applying drugs acting on this system in clinical settings for the treatment of ischemic cardiac disease. This article provides a detailed analysis of how the ET-1 system is involved in the regulation of carrier-mediated NE release from sympathetic nerve endings in protracted myocardial ischemia.
    Cardiology research and practice. 01/2012; 2012:789071.
  • Source
    Kento Kitada, Mamoru Ohkita, Yasuo Matsumura
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of the endothelin (ET)-1/ET receptor system is involved in the development of vascular diseases such as atherosclerosis, vascular hypertrophy, and restenosis. Some issues still remain unresolved including whether ET receptor antagonists are expected to become the new therapeutic tools for the treatment of vascular diseases. One of the unresolved critical points is the functional role of ET receptor subtypes on each vascular disease, in particular the pathophysiological roles of the ET(B) receptor. We recently demonstrated that selective inhibition of the ET(B) receptor system showed harmful effects in the development of neointimal formation after vascular injury. However, there was no apparent difference in the therapeutic effects between a nonselective ET(A)/ET(B) receptor antagonist and selective ET(A) receptor antagonist. These findings indicate that antagonism of the ET(A) receptor system is essential for suppressing vascular remodeling, irrespective of the presence of ET(B)-receptor-mediated actions, although the selective ET(B) receptor antagonist worsens vascular remodeling. In addition, we found that ET receptor systems contribute to sex differences in the severity of vascular disease, thereby suggesting that the efficacy of ET receptor antagonists for vascular diseases may differ between sexes. In this paper, we outline the roles of the ET-1/ET(B) receptor system on vascular diseases and its sex differences.
    Cardiology research and practice. 01/2012; 2012:731970.
  • [Show abstract] [Hide abstract]
    ABSTRACT: GGsTop [2-amino-4-{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid], is a novel, highly selective, and irreversible γ-glutamyl transpeptidase (GGT) inhibitor with no inhibitory activity on glutamine amidotransferases. In this study, we investigated the effects of treatment with GGsTop on ischemia/reperfusion-induced renal injury in uninephrectomized rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 1 day after reperfusion. Treatment with GGsTop (1 and 10 mg/kg i.v.) 5 min before ischemia attenuated the ischemia/reperfusion-induced renal dysfunction in a dose-dependent manner. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which was significantly suppressed by the GGsTop treatment. In renal tissues exposed to ischemia/reperfusion, GGT activity was markedly increased immediately after reperfusion, whereas renal superoxide production and malondialdehyde level were significantly increased 6 h after reperfusion. These alterations were abolished by the treatment with GGsTop. In addition, renal glutathione content was decreased by the 45-min ischemia, but its level was markedly elevated by the GGsTop treatment. Our results demonstrate that the novel and highly selective GGT inhibitor GGsTop prevents ischemia/reperfusion-induced AKI. The renoprotective effect of GGsTop seems to be attributed to the suppression of oxidative stress by inhibiting GGT activation, thereby preventing the degradation of glutathione.
    Journal of Pharmacology and Experimental Therapeutics 09/2011; 339(3):945-51. · 3.89 Impact Factor

Publication Stats

3k Citations
628.51 Total Impact Points

Institutions

  • 1986–2014
    • Osaka University of Pharmaceutical Sciences
      • • Laboratory of Pathological and Molecular Pharmacology
      • • Department of Pharmacology
      Ōsaka, Ōsaka, Japan
  • 2013
    • Osaka Ohtani University
      • Faculty of Pharmacy
      Ōsaka-shi, Osaka-fu, Japan
  • 2011
    • Hyogo University of Health Sciences
      Kōbe, Hyōgo, Japan
  • 2005–2010
    • Osaka Medical College
      • First Department of Internal Medicine
      Takatuki, Ōsaka, Japan
  • 1988
    • Osaka City University
      • Department of Radiology
      Ōsaka, Ōsaka, Japan