Combination of miglitol, an anti-diabetic drug, and nicorandil markedly reduces myocardial infarct size through opening the mitochondrial K(ATP) channels in rabbits.
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The anti-diabetic drug miglitol, an alpha-glucosidase inhibitor, which is currently used clinically, reduces myocardial infarct size by reducing the glycogenolytic rate through inhibition of the alpha-1,6-glucosidase of glycogen-debranching enzyme in the heart. Nicorandil, a K(ATP) channel opener with a nitrate-like effect, which is also currently used clinically, also reduces the infarct size. Therefore, we hypothesized that combination of nicorandil and submaximal dose of miglitol could markedly reduce myocardial infarct size more than miglitol or nicorandil alone, and investigated the mechanism for the infarct size-reducing effect. Japanese white rabbits without collateral circulation were subjected to 30 min coronary occlusion followed by 48 h reperfusion. Pre-ischaemic treatment with submaximal dose of miglitol (5 mg kg(-1), i.v.) and nicorandil alone (100 microg kg(-1) min(-1) 5 min) moderately reduced the infarct size as a percentage of area at risk (24+/-4 and 25+/-4%, respectively), and 10 mg kg(-1) of miglitol markedly reduced the infarct size (15+/-2%) compared with the controls (42+/-2%). Combination of 5 mg kg(-1) of miglitol and nicorandil (100 microg kg(-1) min(-1) 5 min), and 10 mg kg(-1) of miglitol and nicorandil (100 microg kg(-1) min(-1) 5 min) significantly reduced the infarct size (13+/-4 and 12+/-3%, respectively) more than miglitol or nicorandil alone. Pretreatment with 5HD completely abolished the infarct size-reducing effect of 10 mg kg(-1) of miglitol alone (36+/-7%) and that of combination of 5 mg kg(-1) of miglitol and nicorandil (46+/-2%). Combination of nicorandil and submaximal dose of miglitol markedly reduced the myocardial infarct size more than miglitol or nicorandil alone. This effect was suggested to be related to the opening of mitochondrial K(ATP) channels. (+info)
Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone.
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The potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male erectile dysfunction has recently been suggested based on positive clinical outcomes following intra-cavernosal administration of pinacidil. Agents that increase the levels of cGMP via elevation of nitric oxide (NO) nitroglycerin, for example, are also effective in improving erectile function preclinically and clinically. The aim of the present study was to determine the effects and mechanism of the action of nicorandil on rabbit corpus cavernosum. The in vitro regulation of smooth muscle tone was assessed in isolated cavernosal tissues pre-contracted with phenylephrine. Nicorandil, but not its major metabolite, relaxed phenylephrine-precontracted cavernosum smooth muscle with an EC(50) of 15 microM. The effects of nicorandil were only partially reversed by the K(ATP) channel blocker glyburide (10 microM) or by a soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 microM). However, a combination of ODQ and glyburide completely blocked the relaxant effects of nicorandil. The results of the present study indicate that nicorandil can relax rabbit cavernosal tissue in vitro via a mechanism that involves activation of K(ATP) channels and stimulation of soluble guanylate cyclase. (+info)
ATP-Sensitive potassium channels modulate glucose transport in cultured human skeletal muscle cells.
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Several lines of evidence suggest that ATP-sensitive potassium (KATP) channels are involved in glucose uptake by insulin target tissues. The aim of the present study was to prove directly the effect of KATP channel activity on glucose transport into cultured human skeletal muscle cells. We used potassium channel openers PCO-400 and nicorandil alone or in combination with channel blockers glibenclamide and gliclazide to examine their effects on insulin- or high glucose concentration-induced glucose uptake using 2-deoxy-D-3H-glucose or 3-O-methyl-D-3H-glucose as tracer, respectively. PCO-400 inhibited the basal (non-stimulated) uptake of 2-DG or 3-OMG at the glucose concentration of 5 mM. PCO-400 and nicorandil dose-dependently inhibited insulin-stimulated glucose uptake, and their inhibitory effects were reversed by glibenclamide or gliclazide. In addition, PCO-400 inhibited high glucose concentration-facilitated glucose transport in the absence of insulin, and this effect was also antagonized by both sulfonylurea drugs. Regarding the mechanism by which KATP channels modulate glucose transport, we focused on protein kinase C (PKC), because PKC has been supposed to participate in both insulin- and high glucose concentration-stimulated glucose transport. PMA (phorbol 12-myristate 13-acetate) dose-dependently reversed the PCO-400-induced suppression of insulin-stimulated glucose uptake. On the other hand, PCO-400 at the concentration that inhibited glucose uptake caused no alteration of membrane-associated PKC activity in the presence of insulin or PMA. From these results we conclude that KATP channels modulate the basal and insulin-or high glucose level-stimulated glucose transport in skeletal muscle through a mechanism independent of PKC. (+info)
Ischemic preconditioning attenuates cardiac sympathetic nerve injury via ATP-sensitive potassium channels during myocardial ischemia.
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BACKGROUND: During myocardial ischemia, massive norepinephrine (NE) is released from the cardiac sympathetic nerve terminals, reflecting the sympathetic nerve injury. A brief preceding ischemia can reduce infarct size; this is known as ischemic preconditioning (PC). The effect of PC on sympathetic nerves, however, including its underlying mechanisms in dog hearts, has remained unclear. Thus, this study was designed to elucidate whether the activation of ATP-sensitive potassium (K(ATP)) channels is involved in the mechanism of cardiac sympathetic nerve protection conferred by PC. METHODS AND RESULTS: Interstitial NE concentration was measured by the in situ cardiac microdialysis method in 45 anesthetized dogs. Five minutes of ischemia followed by 5 minutes of reperfusion was performed as PC. In the controls, the dialysate NE concentration (dNE) increased 15-fold after the 40-minute ischemia. PC decreased dNE at 40-minute ischemia by 59% (P<0.01), which was reversed by glibenclamide. A K(ATP) channel opener, nicorandil (25 microg. kg(-1). min(-1) IV), decreased dNE at 40 minutes of ischemia by 76% (P<0.01), which was also reversed by glibenclamide. During the PC procedure, no significant increase in dNE was detected, even with the uptake-1 inhibitor desipramine. CONCLUSIONS: Cardiac sympathetic nerve injury during myocardial ischemia was attenuated by PC via the activation of K(ATP) channels, but the trigger of the PC effect is unlikely to be NE release in dog hearts. (+info)
Dose-dependent prophylactic effect of nicorandil, an ATP-sensitive potassium channel opener, on intra-operative myocardial ischaemia in patients undergoing major abdominal surgery.
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Nicorandil, a nicotinamide nitrate derivative, relaxes vascular smooth muscle and reduces cardiac muscle contractility by increasing membrane potassium conductance, probably by activating ATP-sensitive potassium channels. In this prospective, randomized, double-blind, placebo-controlled clinical study, we examined the dose-dependent prophylactic effect of nicorandil on intra-operative myocardial ischaemia in 248 patients who had pre-operative risk factors for ischaemic heart disease and were undergoing major abdominal surgery. Patients in group HD (n=81) received a bolus dose of nicorandil 0.08 mg kg(-1) and a continuous infusion of 0.08 mg kg(-1) h(-1). Patients in group LD (n=87) received nicorandil 0.04 mg kg(-1) and 0.04 mg kg(-1) h(-1). Patients in the placebo (P) group (n=80) received the same volumes of saline. The patients were monitored with a three-lead clinical ECG monitor with an ST trending device from arrival in the operating theatre to the end of anaesthesia. Intra-operative myocardial ischaemia occurred significantly less frequently in the HD group (one patient, 1.2%) than in the LD (11 patients, 12.6%) and P groups (21 patients, 26.3%) (P<0.01), and in group LD significantly less than in group P (P<0.05). Administration of nicorandil had little effect on the patients' heart rate or arterial pressure. Three patients in group P and none in either treatment group developed myocardial infarction after surgery. (+info)
Structural basis for the interference between nicorandil and sulfonylurea action.
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Nicorandil is a new antianginal agent that potentially may be used to treat the cardiovascular side effects of diabetes. It is both a nitric oxide donor and an opener of ATP-sensitive K(+) (K(ATP)) channels in muscle and thereby causes vasodilation of the coronary vasculature. The aim of this study was to investigate the domains of the K(ATP) channel involved in nicorandil activity and to determine whether nicorandil interacts with hypoglycemic sulfonylureas that target K(ATP) channels in pancreatic beta-cells. K(ATP) channels in muscle and beta-cells share a common pore-forming subunit, Kir6.2, but possess alternative sulfonylurea receptors (SURs; SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle). We expressed recombinant K(ATP) channels in Xenopus oocytes and measured the effects of drugs and nucleotides by recording macroscopic currents in excised membrane patches. Nicorandil activated Kir6.2/SUR2A and Kir6.2/SUR2B but not Kir6.2/SUR1 currents, consistent with its specificity for cardiac and smooth muscle K(ATP) channels. Drug activity depended on the presence of intracellular nucleotides and was impaired when the Walker A lysine residues were mutated in either nucleotide-binding domain of SUR2. Chimeric studies showed that the COOH-terminal group of transmembrane helices (TMs), especially TM 17, is responsible for the specificity of nicorandil for channels containing SUR2. The splice variation between SUR2A and SUR2B altered the off-rate of the nicorandil response. Finally, we showed that nicorandil activity was unaffected by gliclazide, which specifically blocks SUR1-type K(ATP) channels, but was severely impaired by glibenclamide and glimepiride, which target both SUR1 and SUR2-type K(ATP) channels. (+info)
Effects of ischemic preconditioning on reperfusion arrhythmias and electrophysiology in isolated rat hearts: it is not a role of KATP(+) channels.
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OBJECTIVE: To investigate the effects of ischemic preconditioning (PC) and ATP sensitive K+ channels (KATP(+) opener nicorandil on reperfusion arrhythmias and electrophysiology. METHODS: Langendorff-perfused rat hearts were subjected to ischemic PC with three cycles of 2 minutes of global ischemia or infusion of KATP(+) opener nicorandil with subsequent 5 minutes global ischemia and reperfusion. The incidence of reperfusion arrhythmias, ventricular fibrillation threshold (VFT), effective refractory period (ERP) and monophasic action potential duration (MAPD) of the left and right ventricles were compared to those from control rat hearts. RESULTS: The results indicated that PC reduced the incidence of total arrhythmias and ventricular fibrillation during reperfusion (P < 0.05, vs controls). PC markedly delayed the onset of arrhythmia after reperfusion (P < 0.01, vs controls). PC significantly enhanced the VFT values during reperfusion and shortened the ERP and the MAPD during ischemia. VFT was restored more rapidly than that in controls. KATP+ opener nicorandil neither reduced the incidence of total arrhythmias and VF nor delayed arrhythmia onset. Nicorandil shortened ERP and MAPD90 without enhancing the VFT values, and VFT returned to normal as slowly as that in controls. CONCLUSIONS: We conclude that PC protects the globally ischemic rat hearts from reperfusion arrhythmias. The antiarrhythmic effect of PC is likely to be related to a significant increase of VFT. KATP(+) opener nicorandil has no potential antiarrhythmic action and KATP(+) channels may not play a major role in the antiarrhythmic effects of ischemic PC in isolated rat hearts. (+info)
Additive effects of nicorandil on coronary blood flow during continuous administration of nitroglycerin.
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OBJECTIVES: We examined whether patients with ischemic heart disease (IHD) should be treated with nicorandil, an adenosine triphosphate-sensitive potassium channel opener, in addition to the regular use of nitrates. BACKGROUND: It has been reported that nicorandil possibly has additive effects on nitroglycerin (NTG) treatment for angina, but the mechanism is not clear. METHODS: We directly measured anterograde coronary blood flow (CBF) with a Doppler guide wire to examine the effects of intravenous administration of NTG (0.3 mg) and nicorandil (6 mg) during continuous administration of NTG at a sufficient dose (25 microg/min) in subjects with normal and stenotic coronary arteries. RESULTS: Additional systemic administration of NTG decreased anterograde CBF (normal -19.7%; stenotic -21.2%). In contrast, nicorandil increased anterograde CBF in both normal (54.6%) and stenotic (89.6%) coronary arteries, without the coronary steal phenomenon. There was a tendency toward nicorandil-dilated diameters in the patients with stenotic arteries (p = 0.06). There were no effects of additional administration on pulmonary artery wedge pressure. There was no difference in changes in heart rate and mean aortic blood pressure between NTG and nicorandil therapy. CONCLUSIONS: These results suggest that in patients treated with nitrates, additional administration of nicorandil is more useful, in terms of increasing CBF, than additional administration of nitrates. Adjunctive use of nicorandil with nitrates may provide the further benefit of myocardial protection and may improve the prognosis of patients with IHD. (+info)