Effects of K+ Channel Opener WAY120491 on Renal Function in Rabbits / 대한신장학회잡지

BACKGROUND: K+ channel opener has been considered as a vasorelaxing agent working through hyperpolarization of vascular smooth muscle cells. Renal tubules-proximal, thick ascending limb of Henle and cortical collecting duct-are the site of the diversity of the K+ channel. ATP-sensitive K+ channel has been observed in the apical membranes of the thick ascending limb of Henle and collecting duct, and basolateral membrane of the proximal tubule. It was also shown that K+ channel opener increased renal hemodynamics and elicited diuretic and natriuretic effects. METHODS: To clarify the renal effects of WAY120491, a K+ channel opener, experiments were performed in unanesthetized normotensive and renal hypertensive rabbits allowing unilateral renal arterial infusion of agent. RESULTS: Intrarenal arterial infusion (0.13, 0.32 and 0.64 microgram/kg/min) of WAY120491 increaased CPAH, CCr, urine volume, UNaV, UKV and CH2O. Renal hemodynamic effects and increments of urine volume and free water clearance were completely blocked by glibenclamide (8.2 g/kg/min), while increments of UNaV and FENa were not significantly affected. Renal hemodynamic and tubular effects of WAY120491 were not significantly different in two-kidney one clip Goldblatt hypertensive rabbits from sham-operated rabbits. CONCLUSIONS: These results suggest that WAY120491 elicits renal effects through ATP-sensitive K+ channel in the renal vasculatures and renal tubules and the renal effects of WAT120491 may not be altered in the hypertension.

Pharmacological evidence that cromakalim inhibits Ca2+ release from intracellular stores in porcine coronary artery

In the present study, it was aimed to further identify the intracellular action mechanism of cromakalim and levcromakaliin in the porcine coronary artery. In intact porcine coronary arterial strips loaded with fura-2/AM, acetylcholine caused an increase in intracellular free Ca2+ ((Ca2+)-i) in association with a contraction in a concentration-dependent manner. Cromakalim (1 micrometer) caused a reduction in acetylcholine-induced increased (Ca2+)-i not only in the normal physiological salt solution (PSS) but also in Ca2+ -free PSS (containing 1mM EGTA). In the skinned strips prepared by exposure of tissue to 20 micrometer beta-escin, inositol 1,4,5-trisphosphate (IP-3) evoked an increase in (Ca2+)-i but it was without effect on the intact strips. The IP-3-induced increase in (Ca2+)-i was inhibited by cromakalim by 78% and levcromakalim by 59% (1 micrometer, each). Pretreatment with glibenclamide (a blocker of ATP-sensitive K+ channels, 10 micrometer and apamin (a blocker of small conductance Ca2+/-activated K+ channels, 1 micrometer strongly blocked the effect of cromakalim and levcromakalim. However, charybdotoxin (a blocker of large conductance Ca2+ -activated K+ channels, 1-micrometer) was without effect. In addition, cromakalim inhibited the GTP-gamma-S (100 micrometer, nonhydrolysable analogue of GTP)-induced increase in (Ca2+)-i. Based on these results, it is suggested that cromakalim and levcromakalim exert a potent vasorelaxation, in part, by acting on the K+ channels of the intracellular sites (e.g., sarcoplasmic reticulum membrane), thereby, resulting in decrease in release of Ca2+ from the intracellular storage site.