CARDIOVASCULAR EFFECTS OF KRN2391 IN ANESTHETIZED DOGS - A COMPARISONWITH CROMAKALIM AND NITROGLYCERIN

The cardiovascular effects of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-p yridine carboximidamide monomethanesulfonate, were compared with those of cromakalim and nitroglycerin in anesthetized dogs. KRN2391 (3-30 m ug/kg, i.v.), cromakalim (3-30 mug/kg, i.v.) and nitroglycerin (1-10 m ug/kg, i.v.) produced a dose-related decrease of the mean blood pressu re with concomitant increase in heart rate. The increase in heart rate caused by cromakalim was lower than that caused by KRN2391 and nitrog lycerin. Left ventricular end-diastolic pressure was decreased by all doses of KRN2398 and nitroglycerin. Cromakalim at 3 and 10 mug/kg decr eased this end-diastolic pressure but increased it at 30 mug/kg. Left ventricular dP/dt was increased by KRN2391 and nitroglycerin but was d ecreased by cromakalim. KRN2391 and cromakalim produced a dose-depende nt increase in aortic and coronary blood flow. Nitroglycerin showed bi phasic changes in aortic and coronary blood flow, i.e., an initial inc rease followed by a decrease. At equipotent hypotensive doses, the inc rease in coronary blood flow induced by KRN2391 was greater than that by cromakalim and nitroglycerin, and total peripheral and coronary vas cular resistances were decreased by KRN2391 and cromakalim. Nitroglyce rin showed biphasic changes in total peripheral and coronary vascular resistances, i.e., these resistances showed an initial decrease follow ed by an increase. The relative decrease of coronary vascular resistan ce compared to the total peripheral vascular resistance was greater fo r KRN2391 than for cromakalim and nitroglycerin. The changes in hemody namic parameters caused by KRN2391 were inhibited by pretreatment with glibenclamide (5 mg/kg, i.v.). These results suggest that the hemodyn amic profile of KRN2391 is closer to that of cromakalim than to that o f nitroglycerin, but that the selectivity for the coronary vascular be d is higher for KRN2391 than for cromakalim. In addition, it is consid ered that, compared with KRN2391 and nitroglycerin, cromakalim has a l ow selectivity for the vasculature vs the myocardium.