HMR 1883, a cardioselective K(ATP) channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats.
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.
Wirth
K J
KJ
DG Cardiovascular Diseases, Hoechst Marion Roussel, Frankfurt am Main, Germany. Klaus.Wirth@hmrag.com
Klaus
E
E
Englert
H G
HG
Schölkens
B A
BA
Linz
W
W
D000255:Adenosine Triphosphate / Q000502:physiology; D000284:Administration, Oral; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000401:mortality; D001157:Arterial Occlusive Diseases / Q000503:physiopathology / Q000517:prevention & control; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D026902:Potassium Channel Blockers; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
D001786:Blood Glucose; D007328:Insulin; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D000255:Adenosine Triphosphate; C114623:clamikalant; D013890:Thiourea; D005905:Glyburide