K(ATP) channel activity is required for hatching in Xenopus embryos.
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A growing body of work suggests that the activity of ion channels and pumps is an important regulatory factor in embryonic development. We are beginning to identify functional roles for proteins suggested by a survey of expression of ion channel and pump genes in Xenopus and chick embryos (Rutenberg et al. [2002] Dev Dyn 225, this issue). Here, we report that the ATP-sensitive K(+) channel protein is present in the hatching gland of Xenopus embryos; moreover, we show that its activity is necessary for hatching in Xenopus. Pharmacologic inhibition of K(ATP) channels not only specifically prevents the hatching process but also greatly reduces the endogenous expression of Connexin-30 in the hatching gland. Based on recent work which showed that gap-junctional communication mediated by Cx30 in the hatching gland was required for secretion of the hatching enzyme, we propose that K(ATP) channel activity is upstream of Cx30 expression and represents a necessary endogenous step in the hatching of the Xenopus embryo. (+info)
Opening of potassium channels modulates mitochondrial function in rat skeletal muscle.
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We have investigated the presence of diazoxide- and nicorandil-activated K+ channels in rat skeletal muscle. Activation of potassium transport in the rat skeletal muscle myoblast cell line L6 caused a stimulation of cellular oxygen consumption, implying a mitochondrial effect. Working with isolated rat skeletal muscle mitochondria, both potassium channel openers (KCOs) stimulate respiration, depolarize the mitochondrial inner membrane and lead to oxidation of the mitochondrial NAD-system in a strict potassium-dependent manner. This is a strong indication for KCO-mediated stimulation of potassium transport at the mitochondrial inner membrane. Moreover, the potassium-specific effects of both diazoxide and nicorandil on oxidative phosphorylation in skeletal muscle mitochondria were completely abolished by the antidiabetic sulfonylurea derivative glibenclamide, a well-known inhibitor of ATP-regulated potassium channels (K(ATP) channels). Since both diazoxide and nicorandil facilitated swelling of de-energised mitochondria in KSCN buffer at the same concentrations, our results implicate the presence of a mitochondrial ATP-regulated potassium channel (mitoK(ATP) channel) in rat skeletal muscle which can modulate mitochondrial oxidative phosphorylation. (+info)
Effect of intracoronary nicorandil administration on preventing no-reflow/slow flow phenomenon during rotational atherectomy.
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A major limitation of the rotational atherectomy (RA) procedure is the occurrence of the no-reflow/slow flow phenomenon and the optimal strategy is still evolving. Recent clinical studies have demonstrated the beneficial effects of nicorandil, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on no-reflow in patients with acute myocardial infarction. The purpose of this study was to evaluate the effect of nicorandil on no-reflow/slow flow phenomenon during RA procedures. Sixty-one patients who underwent RA of complex coronary lesions were randomly divided into 2 groups: (i) nicorandil cocktail (n=24 patients, 37 lesions) and (ii) verapamil cocktail (n=37 patients, 63 lesions). In each group, the drug cocktail mixed with pressurized saline was infused through the 4Fr Teflon sheath of the rotablator system during the RA procedure. In the nicorandil group, the drug cocktail consisted of 24 mg of nicorandil, 5 mg of nitroglycerin, and 10,000 U of heparin. In the verapamil group, the drug cocktail consisted of 10 mg of verapamil, 5 mg of nitroglycerin, and 10,000 U of heparin. Baseline and procedure characteristics did not differ between the 2 groups. RA was performed successfully, and death, Q-wave myocardial infarction, or emergency coronary artery bypass surgery did not occur in any patients. The no-reflow/slow flow phenomenon was observed in 11/63 (17.4%) lesions of the verapamil group, but in only 1/37 (2.7%) lesions of the nicorandil group (p=0.03). No untoward complications were observed during nicorandil infusion. These data indicate that the intracoronary continuous infusion of nicorandil during RA procedures is easy and safe, and prevents no-reflow/slow flow phenomenon more effectively than infusion of verapamil. (+info)
Haemodynamic and electrocardiographic consequences of severe nicorandil toxicity.
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A 35 year old woman was admitted to the emergency department two hours after ingesting 60x20 mg tablets of nicorandil, total 1.2 g. The dominant feature of icorandil toxicity was profound peripheral vasodilatation associated with coronary hypoperfusion. Despite widespread electrocardiographic signs of myocardial ischaemia, there was no evidence of myocardial damage and no serious cardiac arrhythmia. Volume loading and pressor support proved to be an effective treatment strategy. (+info)
Modulation of slow waves by hyperpolarization with potassium channel openers in antral smooth muscle of the guinea-pig stomach.
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Modulation of spontaneous electrical activities (slow waves, pacemaker potentials and follower potentials) in response to hyperpolarization produced by the ATP-sensitive K+ channel openers (KCOs) pinacidil or nicorandil was investigated in smooth muscle tissues of the guinea-pig stomach antrum. With hyperpolarization, the amplitude of slow waves and follower potentials was reduced and that of pacemaker potentials was increased, with a minor modulation of their frequency. The attenuation of slow waves was associated with an inhibition of the 1st component and abolition of the 2nd component. All these actions of KCOs were antagonized by glibenclamide. An increase in the extracellular K+ concentration prevented the KCO-induced hyperpolarization with partial restoration of slow waves, suggesting that the inhibition was produced mainly by a decrease in membrane resistance. Exposure of tissues to KCOs for a long period of time (> 20 min) resulted in the reappearance of slow waves displaying both 1st and 2nd components. The 2nd component of the slow wave, which displayed a slower recovery, was inhibited again by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-sensitive K+ channels. Noradrenaline hyperpolarized the membrane by activating apamin-sensitive K+ channels and increased the amplitude and frequency of slow waves through activation of alpha 1-adrenoceptors, actions different from those of KCOs. Thus, inhibition of slow waves by KCOs may be primarily related to the decrease in amplitude of a passive electrotonic component, possibly due to a reduction of the input resistance. The hyperpolarization shifted the threshold potential for generation of the 2nd component of slow waves to negative levels, presumably due to modulation of mitochondrial functions. (+info)
Usefulness of massive oral nicorandil in a patient with variant angina refractory to conventional treatment.
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A 67-year-old man, who was previously diagnosed with vasospastic angina and treated with standard therapy, was admitted to our hospital because of recurrent chest pain refractory to sublingual nitroglycerin. Admission electrocardiography revealed ST segment elevation in II, III and aV(F), and his symptoms were relieved by intravenous bolus administration of nicorandil. He was diagnosed to have active variant angina, and remained symptomatic even after treatment with calcium antagonists and nitrates at optimal doses. Intravenous bolus administration of nicorandil was consistently effective to relieve his symptoms. Anginal attack was finally prevented by massive oral nicorandil in addition to conventional treatment. (+info)
Intravenous nicorandil in conjunction with coronary reperfusion therapy is associated with better clinical and functional outcomes in patients with acute myocardial infarction.
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The aim of this retrospective study was to assess whether intravenous nicorandil, a hybrid of NO and a KATP channel opener, in conjunction with percutaneous coronary intervention (PCI) improves the long-term prognosis in patients with acute myocardial infarction (AMI). Intravenous nicorandil has already been shown to improve the in-hospital prognosis of patients with anterior AMI. The study population consisted of 272 patients with a reperfused AMI who were admitted during a similar time interval, before (control; n=114) and after nicorandil treatment (n=158). In the nicorandil group, a 4 mg bolus injection was given, followed by 6 mg/h infusion for 24 h and then oral nicorandil at 15 mg/day for at least 1 month. In the patients with an anterior AMI, left ventricular (LV) function was better and the frequency of LV remodeling was lower after 3 months in the nicorandil group; however, in those with a non-anterior AMI, there were no differences in functional outcome and the frequency of LV remodeling between the 2 groups. The frequency of cardiac events was significantly lower in the nicorandil group, and the use of nicorandil was derived as a potential factor related to freedom from cardiac events (p<0.01, odds ratio = 0.27). Nicorandil treatment was associated with better myocardial perfusion and a better functional and clinical outcome than PCI alone, and this beneficial effect was maintained for a long time, particularly in patients with anterior AMI. (+info)
Oral nicorandil recaptures the waned protection from preconditioning in vivo.
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1. Protection from preconditioning (PC) wanes and is eventually lost when multiple bouts of short ischemia or a prolonged reperfusion interval precedes the following sustained ischemia. The activation of mitochondrial K(ATP) channels plays a pivotal role in the intracellular signaling of PC. We tested whether the K(ATP) channel opener nicorandil (nic) preserves the given protection from PC in conditions where this benefit decays and is lost. 2. Eight groups of rabbits were divided into two equal series of experiments, one without nic (placebo) and one with nic treatment. Nic was given orally for 5 consecutive days in a dose of 5 mg kg(-1) d(-1). In a second step, four additional groups were treated with nic plus the K(ATP) channel blocker 5HD and 1 additional control group with nitroglycerin only. All the animals were anesthetized and then subjected to 30 min of myocardial ischemia and 2 h of reperfusion with one of the following interventions before the sustained ischemia: Control groups to no intervention; 3PC groups to three cycles of 5-min ischemia-10-min reperfusion; 8PC groups to eight cycles of 5-min ischemia - 10-min reperfusion; and 3PC90 groups to the same interventions as the 3PC groups but with a prolonged (90 min) intervening reperfusion interval before the sustained ischemia. The infarcted and the risk areas were expressed in percent. 3. There was no significant change in infarct size between the placebo, the nic and the 5HD-nic in the control groups (41.5+/-4.7, 43.9+/-7.1 and 48.7+/-6.4%) and 3PC groups (10.3+/-3.4, 12.2+/-3.9 and 12.6+/-4.5%). However, there was a significant decrease after nic treatment in groups 8PC (47.7+/-8.8% vs 13.0+/-2.6%, P<0.01) and 3PC90 (37.3+/-6.0% vs 14.2+/-2.4%, P<0.01), which was abrogated (38.2+/-4.7 and 42.7+/-4.4%, respectively, for 8PC and 3PC90 groups). Nitroglycerin had no effect on infarct size (39.1+/-3.1%, P=NS vs other controls). 4. Oral treatment with nic recaptures the waned protection of PC, both after repetitive bouts of short ischemia or after a prolonged reperfusion interval, preserving the initially obtained benefit. Nic by itself is insufficient to initiate PC in vivo. (+info)