Regional hemodynamic dose-response of lemakalim and glybenclamide in anesthetized rats.

Abstract

Studies were undertaken to establish the regional hemodynamic profile and dose-response relation of the adenosine triphosphate (ATP)-dependent potassium channel activator lemakalim in anesthetized rats. In addition, the ability of the sulphonylurea potassium channel blocker glybenclamide to reverse the hemodynamic effects of an infusion of lemakalim was determined. Studies were performed in anesthetized rats instrumented to measure arterial pressure, heart rate, and hemodynamics in the coronary, mesenteric, renal, and hindquarters vascular beds. One group of rats (n = 5) received increasing intravenous infusion rates of the potassium channel activator lemakalim. The doses administered were 0.1, 0.3, 1.0, 3.0, and 10 micrograms/kg/min, and each dose was infused until steady-stateresponses were achieved. Dose-related decreases in mean arterial pressure were observed with the first significant effect occurring at 1 microgram/kg/min. The hindquarters bed was the most sensitive of the four beds measured. Vascular resistance was significantly decreased in this bed with an infusion of 0.3 microgram/kg/min i.v. lemakalim. In addition, this vascular bed was the only one to demonstrate significant increases in blood flow over baseline. Significant reductions in vascular resistance were observed over the dose range of 1-10 micrograms/kg/min for both the coronary and renal vascular beds. The mesenteric bed was less sensitive in that the first significant reduction in resistance was not observed until the infusion dose was increased to 3 micrograms/kg/min. The other group of rats (n = 5) was used to determine the dose-response relation of glybenclamide. These rats received an intravenous infusion of lemakalim at 1 microgram/kg/min to establish a moderate cardiovascular effect. Ascending cumulative intravenous injections of glybenclamide from 0.3 to 30 mg/kg were then administered. The lowest dose, 0.3 mg/kg, significantly attenuated the depressor response to the lemakalim infusion, but the response was not fully reversed until the dose of glybenclamide reached 10 mg/kg i.v.. Doses > 10 mg/kg i.v. of glybenclamide were required for complete reversal of the hemodynamic responses to this dose of lemakalim. Therefore lemakalim exerts vasodilatory properties in each of the beds measured but demonstrates a selectivity for the hindquarters. The results with glybenclamide demonstrate also that the responses to lemakalim are the result of activation of the ATP-dependent potassium channel. Last, doses > 10 mg/kg of glybenclamide are required to ensure that ATP-dependent potassium channels are blocked in the circulatory system in rats.