REGIONAL HEMODYNAMIC DOSE-RESPONSE OF LEMAKALIM AND GLYBENCLAMIDE IN ANESTHETIZED RATS

Studies were undertaken to establish the regional hemodynamic profile and dose-response relation of the adenosine triphosphate (ATP)-depende nt potassium channel activator lemakalim in anesthetized rats. In addi tion, the ability of the sulphonylurea potassium channel blocker glybe nclamide to reverse the hemodynamic effects of an infusion of lemakali m was determined. Studies were performed in anesthetized rats instrume nted to measure arterial pressure, heart rate, and hemodynamics in the coronary, mesenteric, renal, and hindquarters vascular beds. One grou p 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 mu g/kg/min, and each dose was infused until s teady-state responses were achieved. Dose-related decreases in mean ar terial pressure were observed with the first significant effect occurr ing at 1 mu g/kg/min. The hindquarters bed was the most sensitive of t he four beds measured. Vascular resistance was significantly decreased in this bed with an infusion of 0.3 mu g/kg/min i.v. lemakalim. In ad dition, this vascular bed was the only one to demonstrate significant increases in blood flow over baseline. Significant reductions in vascu lar resistance were observed over the dose range of 1-10 mu g/kg/min f or both the coronary and renal vascular beds. The mesenteric bed was l ess sensitive in that the first significant reduction in resistance wa s not observed until the infusion dose was increased to 3 mu g/kg/min. The other group of rats (n=5) was used to determine the dose-response relation of glybenclamide. These rats received an intravenous infusio n of lemakalim at 1 mu g/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/k g, significantly attenuated the depressor response to the lemakalim in fusion, but the response was not fully reversed until the dose of glyb enclamide reached 10 mg/kg i.v.. Doses >10 mg/kg i.v. of glybenclamide were required for complete reversal of the hemodynamic responses to t his dose of lemakalim. Therefore lemakalim exerts vasodilatory propert ies in each of the beds measured but demonstrates a selectivity for th e hindquarters. The results with glybenclamide demonstrate also that t he responses to lemakalim are the result of activation of the ATP-depe ndent potassium channel. Last, doses >10 mg/kg of glybenclamide are re quired to ensure that ATP-dependent potassium channels are blocked in the circulatory system in rats.