Tilisolol hydrochloride dilates coronary arteries through an ATP-sensitive K+-channel opening mechanism in dogs

Abstract

Tilisolol is a beta-blocking agent with vasodilatory properties that was recently shown to possess a potassium (K+) channel opening activity. We investigated whether tilisolol has vasodilatory effects on coronary circulation in dogs. Mongrel dogs were chronically instrumented for measurements of circumflex coronary artery diameter (CoD) and coronary blood flow (CBF). We compared the effects of tilisolol on dog coronary arteries with those of two beta-blockers, propranolol and arotinolol. Both propranolol (1 mg/kg, intravenously, i.v.) and arotinolol (0.25 mg/kg, i.v.) decreased CoD and increased coronary vascular resistance (CVR). Tilisolol (2 mg/kg, i.v.) decreased CVR but had no significant effect on CoD. To investigate the mechanism of the coronary action of tilisolol, we examined differences in the response to tilisolol in the absence and presence of glibenclamide, an ATP-sensitive K+ channel blocker. Tilisolol (1,2,4, and 8 mg/kg, i.v.) produced a dose-dependent decrease in CVR without glibenclamide, whereas pretreatment with glibenclamide significantly suppressed this effect. Without glibenclamide, tilisolol had no significant effect on CoD at doses of 1-4 mg/kg (i.v.). However, at the higher dose of 8 mg/kg (i.v.), tilisolol significantly increased CoD (1.00 +/- 0.15%, p < 0.01). After pretreatment with glibenclamide, tilisolol (1-8 mg/kg, i.v.) produced a significant decrease in CoD. Therefore, we concluded that tilisolol exerts its vasodilatory effect on the coronary circulation through an ATP-sensitive K+ channel opening mechanism, and that its vasodilatory action is more prominent in coronary resistance vessels than in large coronary arteries.