TILISOLOL HYDROCHLORIDE DILATES CORONARY-ARTERIES THROUGH AN ATP-SENSITIVE K-CHANNEL OPENING MECHANISM IN DOGS()

Tilisolol is a beta-blocking agent with vasodilatory properties that w as recently shown to possess a potassium (K+) channel opening activity . We investigated whether tilisolol has vasodilatory effects on corona ry circulation in dogs. Mongrel dogs were chronically instrumented for measurements of circumflex coronary artery diameter (CoD) and coronar y blood flow (CBF). We compared the effects of tilisolol on dog corona ry arteries with those of two beta-blockers, propranolol and arotinolo l. Both propranolol (1 mg/kg, intravenously, IV) and arotinolol (0.25 mg/kg, IV) decreased CoD and increased coronary vascular resistance (C VR). Tilisolol (2 mg/kg, IV) decreased CVR but had no significant effe ct on CoD. To investigate the mechanism of the coronary action of tili solol, we examined differences in the response to tilisolol in the abs ence and presence of glibenclamide, an ATP-sensitive K+ channel blocke r. Tilisolol (1,2,4, and 8 mg/kg, IV) produced a dose-dependent decrea se in CVR without glibenclamide, whereas pretreatment with glibenclami de significantly suppressed this effect. Without glibenclamide, tiliso lol had no significant effect on CoD at doses of 1-4 mg/kg (IV). Howev er, at the higher dose of 8 mg/kg (IV), tilisolol significantly increa sed CoD (1.00 +/- 0.15%, p < 0.01). After pretreatment with glibenclam ide, tilisolol (1-8 mg/kg, IV) 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 openi ng mechanism, and that its vasodilatory action is more prominent in co ronary resistance vessels than in large coronary arteries.