HMR 1883, a cardioselective KATP channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats

Abstract

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

“…In contrast to the present results, prior studies in pigs [13], dogs [33,42], rats [43] and rabbits [44] have shown a reduction in ischaemic ventricular fibrillation with the sarcolemmal K ATP blocker HMR 1098 or its congener HMR 1883. The effects of K ATP blockade on ischaemic arrhythmias may depend upon the specific conditions of each experimental model [2].…”

Amiodarone Inhibits Sarcolemmal but Not Mitochondrial KATP Channels in Guinea Pig Ventricular Cells

“…Therefore, sarcK ATP channel blockers ought to be effective in ischemic arrhythmias, by preventing the action potential shortening. This concept is supported by the facts that the selective sarcK ATP channel blocker HMR 1883 effectively prevented ischemia-induced ventricular fibrillation (Billman et al, 1998;Wirth et al, 1999). Blockade of sarcK ATP channels may predispose to aggravate ischemic injury by increasing the Ca 2ϩ influx.…”

“…In this regard, inhibition of sarcK ATP channel may prevent the ischemia-induced shortening of refractory period. In fact, the selective sarcK ATP channel blocker HMR 1883 has been shown to prevent ischemia-induced ventricular fibrillation (Billman et al, 1998;Wirth et al, 1999). On the other hand, inhibition of mitoK ATP channels may produce significant damage to the ischemic myocardium.…”

Effect of the Sarcolemmal KATP Channel Blocker HMR1098 on Arrhythmias Induced by Programmed Electrical Stimulation in Canine Old Myocardial Infarction Model: Comparison With Glibenclamide

“…A newly synthesized sulfonylthiourea, HMR1883, and its sodium salt HMR1098, have selectivity to cardiac sarcolemmal K ATP channels against cardiac mitochondrial, pancreatic b-cell, or vascular smooth muscle K ATP channels (8 -11). The potent antiarrhythmic activity of these compounds has been demonstrated in several animal models of acute myocardial ischemia such as anesthetized rats and pigs (12,13), and post-infarcted conscious dogs (7). In order to investigate whether cardioselective K ATP channel block exerts an antiarrhythmic effect in an old myocardial infarction model, we examined effects of intravenous HMR1098 on the ventricular arrhythmias induced by programmed electrical stimulation (PES) in comparison with a nonselective K ATP channels blocker, glibenclamide.…”

“…Glibenclamide: The effects of glibenclamide on arrhythmias have been investigated in models of acute myocardial ischemia in dogs (7) and acute ischemiareperfusion in rats (12). Those studies showed that this drug is antiarrhythmic at a dose of 1 mg / kg (i.v.).…”