Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide

Background Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that opens voltage-dependent K+ (K-v) channels in peripheral arteries. We studied the role of KCNQ-type K-v channels and tested the hypothesis that hydrogen sulfide (H2S) could be an ADRF. Methods We performed isometric contraction studies on systemic arteries of rats and mice. Results In mesenteric arteries and aortas without perivascular adipose tissue, the KCNQ channel openers retigabine, VRX0530727, VRX0621238, and VRX0621688 produced concentration-dependent vasorelaxation; VRX0621688 was the most potent vasodilator. The KCNQ inhibitor XE991 (30 mu mol/l) blocked the effects of both the drugs and ADRF. Inhibitors of cystathionine gamma lyase (CSE) beta-cyano-L-alanine (BCA, 5 mmol/l) and 4-propargyl glycine (PPG, 10 mmol/l) also blocked the relaxations. CSE is expressed in perivascular adipose tissue and endogenously generates H2S. The H2S donor NaHS produced concentration-dependent vasorelaxation, which was also blocked by XE991. The vasodilatory capacities of retigabine, VRX0530727, VRX0621238, and VRX0621688 were preserved following inhibition of H2S generation in perivascular fat. Conclusion We suggest that KCNQ channel opening is a powerful mechanism to produce vasorelaxation of systemic arteries in rats and mice. Furthermore, KCNQ channels play a major role in the paracrine control of vascular tone by perivascular adipose tissue, which is at least in part mediated or modulated by H2S. In conditions of reduced H2S release from perivascular adipose tissue, these paracrine effects can be mimicked by synthetic KCNQ channel openers. J Hypertens 28:1875-1882 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.