In vitro and in vivo vasodilating effects of KRN4884, Ki1769 and Ki3005, pyridinecarboxamidine derivatives

The vasodilating potencies and mechanism of action of a novel pyridinecarboxamidine derivative, KRN4884 [5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ] were compared with those of Ki1769 [N-cyano-N'-(2-phenylethyl)-3-pyridinecarboxamidine] and Ki3005 [N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine] in rat isolated aortas and in anesthetized normotensive rats. In vitro. KRN4884 (10(-10)-10(-6) M). Ki1769 (10(-8)-10(-5) M) and Ki3005 (10(-10)-10(-6) M) produced concentration-dependent relaxations. KRN4884 was about 100- and 10-fold more potent than Ki1769 and Ki3005, respectively. The relaxant effects of these compounds were antagonized by glibenclamide. In vivo, KRN4884 (1-10 micrograms/kg, intravenously [i.v.]), Ki1769 (10-100 micrograms/kg, i.v.) and Ki3005 (3-30 micrograms/kg, i.v.) produced dose-dependent decreases in mean blood pressure with slight increases in heart rate. At 10 micrograms/kg, i.v., the hypotensive effect of KRN4884 was about the same as that of Ki3005 and about 5-fold more pronounced than that of Ki1769. The hypotensive action remained for a longer period after KRN4884 administration. In rats pre-treated with glibenclamide (20 mg/kg, i.v.), the hypotensive effect of KRN4884 was abolished. These results suggest that the effect of KRN4884 in vitro and in vivo is based on its K channel opening action and that the in vitro vasorelaxant effect of these compounds in aortic rings does not predict their relative hypotensive effect in vivo.