Tomoaki Matsumoto

Sapporo Medical University, Sapporo, Hokkaidō, Japan

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Publications (7)48.53 Total impact

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    ABSTRACT: Reverse-mode activation of the Na+-Ca2+ exchanger (NCX) at the time of reperfusion following ischemia contributes to Ca2+ overload and cardiomyocyte injury. The aim of the present study was to determine whether increased NCX in the myocardium that survived after infarction enhances its vulnerability to ischemia/reperfusion injury. Rabbits were divided into post-MI and sham groups and underwent ligation of the left circumflex coronary artery and sham operation, respectively. Two weeks later, hearts were isolated and perfused with crystalloid in the Langendorff mode with monitoring of left ventricular (LV) pressure. NCX level in the myocardium was determined by Western blotting. Myocardial stunning was induced by 5 episodes of 5-min global ischemia/5-min reperfusion. Using separate groups of hearts, myocardial infarction was induced by 30-min global ischemia/2-h reperfusion with or without treatment with 0.3 microM KB-R7943, a reverse-mode selective blocker of NCX. Heart weight-to-body weight ratio was 20% larger and NCX protein level was 60% higher in the post-MI group than in the sham group. However, there were no significant differences between severities of myocardial stunning after the repetitive ischemia/ reperfusion (18 +/- 7 vs. 25 +/- 2% reduction in LV developed pressure) and between infarct sizes after 30-min ischemia (59.1 +/- 4.1 vs. 63.0 +/- 4.5% of risk area) in the post-MI and sham groups. KB-R7943 limited infarct size in the post-MI group by 53%, and the extent of this protection was not different from that we have reported for hearts without previous infarcts (i.e. 45% reduction of infarct size). These results suggest that enhanced NCX expression does not necessarily increase myocardial vulnerability to myocardial stunning and infarction.
    No preview · Article · Jul 2003 · Molecular and Cellular Biochemistry
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    ABSTRACT: We have recently shown that the protective mechanism of ischemic preconditioning (PC) is impaired in the myocardium that survived infarction and underwent postinfarct ventricular remodeling. In this study, we examined the hypothesis that failure of PC to activate PKC-epsilon underlies the refractoriness of the remodeling heart to PC. Circumflex coronary arteries were ligated in rabbits to induce infarction and subsequent ventricular remodeling, and only sham operations were performed in controls. Hearts were isolated before (i.e. 4 days later) or after (i.e. 2 weeks later) remodeling of the left ventricle and used for isolated buffer-perfused heart experiments. Myocardial infarction was induced in isolated hearts by 30 min global ischemia/2 h reperfusion, and its size was measured by tetrazolium staining. Using separate groups of hearts, tissue biopsies were taken before and after PC, and PKC translocation was assessed by Western blotting. Areas infarcted in vivo by coronary ligation (CL) were excluded from subsequent infarct size/PKC analyses. In the hearts 4 days after CL, PC with 2 cycles of 5 min ischemia/5 min reperfusion induced PKC-epsilon translocation from cytosol to particulate fractions and limited infarct size to 40% of control value. In the hearts remodeled 2 weeks after CL, PC failed to induce PKC-epsilon translocation and infarct size limitation. In this group, PKC activity and hemodynamic responses to adenosine were similar to those in sham-operated controls. When remodeling after CL was prevented by valsartan infusion (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker, PC could induce both infarct limitation and PKC-epsilon translocation. The present results suggest that persistent activation of AT1 receptors during remodeling disturbed the PC signaling between G proteins and PKC-epsilon, which underlies the refractoriness of the remodeled myocardium to PC.
    No preview · Article · Jun 2003 · Molecular and Cellular Biochemistry
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    ABSTRACT: This study aimed to examine:1) whether nicorandil protects the ischemic myocardium by activating sarcolemmal adenosine triphosphate (ATP)-sensitive K(+) (sarcK(ATP)) channels or the mitochondrial K(ATP) (mitoK(ATP)) channels, and 2) whether protein kinase C (PKC) activity is necessary for cardioprotection afforded by nicorandil. Nicorandil is a hybrid of nitrate and a K(ATP) channel opener that activates the sarcK(ATP) and mitoK(ATP) channels. Both of these K(ATP) channels are regulated by PKC, and this kinase may be activated by nitric oxide and also by oxygen free radicals (OFR) generated after mitoK(ATP) channel opening. In isolated rabbit hearts, infarction was induced by 30-min global ischemia/2-h reperfusion with monitoring of the activation recovery interval (ARI), an index of action potential duration. Protein kinase C translocation was assessed by Western blotting. Nicorandil did not change ARI before ischemia, but it accelerated ARI shortening after the onset of ischemia and reduced infarct size by 90%. A sarcK(ATP) channel selective blocker, HMR1098, abolished acceleration of ischemia-induced ARI-shortening by nicorandil and eliminated 40% of nicorandil-induced infarct size limitation. A mitoK(ATP) channel selective blocker, 5-hydroxydecanoate, abolished the protection afforded by nicorandil without affecting ARI. Cardioprotection by nicorandil was inhibited neither by an OFR scavenger, N-2-mercaptopropionylglycine nor by a PKC inhibitor, calphostin C, at a dose that was capable of inhibiting PKC- epsilon translocation after preconditioning. Both the sarcK(ATP) and mitoK(ATP) channels are involved in anti-infarct tolerance afforded by nicorandil, but PKC activation induced by nitric oxide or OFR generation, if any, does not play a crucial role.
    Full-text · Article · Nov 2002 · Journal of the American College of Cardiology
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    ABSTRACT: Objectives This study aimed to examine: 1) whether nicorandil protects the ischemic myocardium by activating sarcolemmal adenosine triphosphate (ATP)-sensitive K+ (sarcKATP) channels or the mitochondrial KATP (mitoKATP) channels, and 2) whether protein kinase C (PKC) activity is necessary for cardioprotection afforded by nicorandil.
    Preview · Article · Oct 2002 · Journal of the American College of Cardiology
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    ABSTRACT: Since the Na(+)-H(+) exchanger (NHE) is not the only pathway of Na(+) influx into cardiomyocytes during ischemia/reperfusion, we hypothesized that blockade of Na(+)-Ca(2+) exchanger (NCX) may be a more efficient strategy than is NHE inhibition for protecting the myocardium from infarction. To test this hypothesis, we compared KB-R7943 (KBR), a novel selective NCX blocker, with cariporide, a selective NHE blocker, with regard to their protective effects against infarction. In isolated rabbit hearts, infarction was induced by 30-min global ischemia/2-h reperfusion, and infarct size was determined by tetrazolium staining and expressed as a percentage of area at risk (%IS/AR). Hearts received no drugs, or were infused with cariporide (1 microM) for 10 min or KBR (0.3 or 10 microM) for 5 min before ischemia or after the onset of reperfusion. Protein level of NCX was assessed by Western blotting. Cariporide infusion before ischemia significantly reduced %IS/AR from 63.9 +/- 2.9% to 20.2 +/- 3.0%, but its infusion upon reperfusion failed to achieve a significant protection (%IS/AR = 53.8 +/- 4.6%). In contrast, KBR infusion similarly reduced infarct size both when infused before ischemia (%IS/AR = 33.3 +/- 6.3% and 21.9 +/- 4.7% by 0.3 and 10 microM KBR, respectively) and when infused for only 5 min after reperfusion (%IS/AR = 35.3 +/- 7.1% and 31.5 +/- 2.1% by 0.3 and 10 microM KBR, respectively). Protein levels of NCX after 30-min ischemia and 30-min ischemia/30-min reperfusion were similar to baseline values in both untreated controls and hearts treated with 0.3 microM KBR upon reperfusion. These results suggest that lethal reperfusion injury is more efficiently suppressed by blockade of the NCX than by blockade of the NHE.
    No preview · Article · Aug 2002 · Cardiovascular Drugs and Therapy
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    ABSTRACT: The present study was designed to assess the relationship between the timing of a mitoK(ATP) channel opener, diazoxide, and its infarct size-limiting effect. In isolated rabbit hearts, infarction was induced by 30 min of global ischemia and 2 h of reperfusion, and infarct size was determined by tetrazolium staining and expressed as a percentage of the left ventricle (%IS/LV). Diazoxide, a mitoK(ATP) channel selective opener, and/or 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel blocker, were infused before or after the onset of ischemia. When these agents were infused during the ischemic period, they were dissolved in a hypoxic buffer at concentrations 10-fold higher than those in the pre-ischemic period, and the infusion rate was set at 2% of the pre-ischemic coronary flow. In untreated controls, %IS/LV was 53.2+/-4.1 (SE). Pretreatment with diazoxide (100 microM) with a 10-min washout period reduced %IS/LV to 7.8+/-2.4 and this protection was abolished by co-infusion of 5-HD (50 microM). Pre-ischemic infusion of diazoxide without a washout period reduced %IS/LV to 7.3+/-1.4, and infusion of diazoxide from 10 min after the onset of ischemia also limited %IS/LV to 14.9+/-4.6. However, diazoxide infusion from 25 min after the onset of ischemia failed to reduce infarct size (%IS/LV = 54.5+/-7.2). Furthermore, pretreatment with 5-HD (50 microM) also completely abolished the protection afforded by early post-ischemic diazoxide infusion (%IS/LV = 48.3+/-6.5). Neither infusion of 5-HD nor the anoxic vehicle alone during ischemia modified %IS/LV. These findings suggest that opening of mitoK(ATP) channels before ischemia and during early ischemia, but not that upon reperfusion, is important for enhancement of myocardial tolerance against infarction.
    No preview · Article · Oct 2001 · Archiv für Kreislaufforschung
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    ABSTRACT: In this study, we examined the possibility that infarct-size limitation by repetitive preconditioning (PC) is achieved by activation of both protein kinase C (PKC) and tyrosine kinase. In addition, we assessed whether such kinase activation is triggered by angiotensin II type 1 (AT1) and alpha1-adrenergic receptors and whether sarcolemmal and mitochondrial adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play roles as effectors of cardioprotection in the rat. Under pentobarbital anesthesia, myocardial infarction was induced by 20-min coronary occlusion and 3-h reperfusion in the rat. Infarct size was determined by tetrazolium and expressed as a percentage of area at risk (%IS/AR). PC with one cycle of 5-min ischemia/5-min reperfusion before 20-min ischemia significantly reduced %IS/AR from the control value of 49.4 +/- 2.0 to 35.4 +/- 2.8, and repetitive PC with two cycles of 5-min ischemia/5-min reperfusion further limited %IS/AR to 3.2 +/-0.9. Infarct-size limitation by single-cycle PC was completely abolished by a PKC inhibitor, staurosporine (100 microg/kg; %IS/ AR, 45.7 +/- 5.0). In contrast, the cardioprotection by repetitive PC was only partially blocked by staurosporine (%IS/AR, 19.8 +/- 2.4), another PKC inhibitor, polymyxin B (5 mg/kg; %IS/AR, 16.2 +/- 3.1), or a tyrosine kinase inhibitor, genistein (5 mg/kg; %IS/AR, 21.8 +/- 1.4). However, a combined injection of genistein and staurosporine additively inhibited protection of repetitive PC (%IS/AR, 36.4 +/- 1.7). Staurosporine, polymyxin B, or genistein alone did not modify %IS/AR in nonpreconditioned rat hearts. Infarct-size limitation by repetitive PC was not attenuated by pretreatment with a selective AT1-receptor blocker (CV11974, 10 mg/kg), prazosin (0.6 mg/kg; %IS/AR, 6.4 +/- 3.2 and 1.6 +/- 0.5, respectively). A selective blocker of mitochondrial K(ATP) channels, 5-hydroxydecanoate (3 mg/kg), completely abolished the cardioprotective effect (%IS/AR, 50.8 +/-3.5), but HMR1883 (3 mg/kg), a selective blocker of sarcolemmal K(ATP) channels, failed to inhibit the preconditioning effect (%IS/AR, 4.4 +/- 0.7). These findings suggest that repetition of PC provokes activation of both PKC and tyrosine kinase, leading to enhanced antiinfarct tolerance by opening of mitochondrial but not sarcolemmal K(ATP) channels. It is unlikely that activation of either AT1 or alpha1-adrenergic receptor alone is crucial to trigger preconditioning. Key Words: Tyrosine kinase-Genistein-Angiotensin II-alpha1-Adrenergic receptor-Sarcolemmal K(ATP) channel-Mitochondrial K(ATP) channel.
    No preview · Article · Apr 2000 · Journal of Cardiovascular Pharmacology