EFFECTS OF KRN4884, A NOVEL K-CHANNEL OPENER, ON THE CARDIOVASCULAR-SYSTEM IN ANESTHETIZED DOGS - A COMPARISON WITH LEVCROMAKALIM, NILVADIPINE, AND NIFEDIPINE

Pharmacological profiles of KRN4884, orophenyl)ethyll-N'-cyano-3-pyrid inecarboxamidine, were evaluated in in vitro and in vivo experiments. In rat isolated aorta, KRN4884 (10-(10)-10(-5) M) produced a concentra tion-dependent relaxation. Pretreatment with glibenclamide (10(-7)-10( -6) M) produced a rightward shift of the concentration-response curve for KRN4884. In anesthetized dogs, KRN4884 (3 and 10 mu g/kg intraveno usly, i.v.), levcromakalim (3 and 10 mu g/kg i.v.), nilvadipine (1-10 mu g/kg i.v.), and nifedipine (1-10 mu g/kg i.v.) produced decreases i n mean blood pressure (MBP), total peripheral vascular resistance (TPR ), and coronary vascular resistance (CVR), and increases in aortic blo od flow (AoF) and coronary blood flow (CBF). The percentage decrease i n CVR was greater than that in TPR with KRN4884 and levcromakalim, but nilvadipine and nifedipine showed no significant differences between CVR and TPR in percentage decreases. Heart rate (HR) was slightly incr eased by KRN4884 but was not affected by levcromakalim, nilvadipine, o r nifedipine. Left ventricular dP/dt (LV dP/dt) was reduced only by ni fedipine in a dose-dependent manner. The duration of the hypotensive a ction of KRN4884 was longer than those of levcromakalim and nifedipine and was similar to that of nilvadipine. The duration of the decreases in TPR and CVR induced by KRN4884 was longer than those induced by le vcromakalim and nifedipine and shorter than that induced by nilvadipin e. These results suggest that the cardiovascular effects of KRN4884 ar e very similar to those of the K channel opener levcromakalim and Ca c hannel blockers such as nilvadipine and nifedipine. However, the hypot ensive effects of KRN4884 are long-acting in comparison with those of levcromakalim and the selective effect of KRN4884 on coronary vasculat ure is greater than those of nilvadipine and nifedipine.