Abstract

BRL 34915 (Cromakalim) is a novel benzopyran that has anti-hypertensive actions. Contractile and 42K efflux responses to BRL 34915 were measured in blood vessels from the rabbit to determine whether Ca-dependent K-channels [K(Ca)] were involved. BRL 34915 increased 42K efflux from all blood vessels tested with an EC50 of 0.2 to 0.7 microM in the superior mesenteric artery (SMA). BRL 34915 also inhibited norepinephrine (NE)-stimulated 42K efflux (96%) and contraction (50%) in SMA with IC50 values (0.2-0.3 microM) which were similar to the EC50. Comparison of two vascular sites showed that the portal mesenteric vein required 10-fold higher BRL 34915 to achieve a 42K response equivalent to the maximal effect on SMA, yet the maximum response to NE was 4-fold greater in portal vein than SMA. The 42K efflux stimulated by BRL 34915 exhibited a significant decrement with time. Ca-removal increased the magnitude and stability of the BRL 34915 response in SMA and femoral arteries, whereas reapplication of Ca in the presence of BRL 34915 caused the 42K efflux to decrease rapidly. These effects of Ca were not altered by nisoldipine (NIS). The 42K efflux stimulated by BRL 34915 and by K-depolarization was additive when applied in combination in SMA. BRL 34915 had no effect on the NIS-inhibited 42K efflux (a Ca-dependent component) during K-depolarization. It is concluded that BRL 34915 acts on K-channels which differ significantly from the known properties of K(Ca)-channels and that BRL 34915 indirectly inhibits NE stimulation of contraction and K(Ca)-channels by hyperpolarizing the smooth muscle membrane.