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, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine+ ++, were evaluated in in vitro and in vivo experiments. In rat isolated aorta, KRN4884 (10(-10)-10(-5) M) produced a concentration-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 micrograms/kg intravenously, i.v.), levcromakalim (3 and 10 micrograms/kg i.v.), nilvadipine (1-10 micrograms/kg i.v.), and nifedipine (1-10 micrograms/kg i.v.) produced decreases in mean blood pressure (MBP), total peripheral vascular resistance (TPR), and coronary vascular resistance (CVR), and increases in aortic blood flow (AoF) and coronary blood flow (CBF). The percentage decrease in 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 increased by KRN4884 but was not affected by levcromakalim, nilvadipine, or nifedipine. Left ventricular dP/dt (LVdP/dt) was reduced only by nifedipine in a dose-dependent manner. The duration of the hypotensive action 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 levcromakalim and nifedipine and shorter than that induced by nilvadipine. These results suggest that the cardiovascular effects of KRN4884 are very similar to those of the K channel opener levcromakalim and Ca channel blockers such as nilvadipine and nifedipine. However, the hypotensive effects of KRN4884 are long-acting in comparison with those of levcromakalim and the selective effect of KRN4884 on coronary vasculature is greater than those of nilvadipine and nifedipine.
D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D019806:Cromakalim; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D002121:Calcium Channel Blockers; C096484:KRN 4884; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D014665:Vasodilator Agents; C035100:nilvadipine; D019806:Cromakalim; D009543:Nifedipine