Involvement of K channels and calcium-independent mechanisms in hydrogen sulfide-induced relaxation of rat mesenteric small arteries.
Journal of Pharmacology and Experimental Therapeutics
American Society for Pharmacology and Experimental Therapeutics (ASPET)
Copyright © 2015 by the American Society for Pharmacology and Experimental Therapeutics
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Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that lowering of calcium and opening of K channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of NaSH, Na2S, and GYY4137 were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free [H2S] than NaSH and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 μM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaSH lowered calcium and caused relaxation of norepinephrine-contracted arteries, while high extracellular potassium reduced NaSH relaxation without corresponding calcium changes. In norepinephrine-contracted arteries, NaSH (1 mM) lowered phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 (MYPT-1) remained unchanged. Inhibitors of guanylate cyclase, protein kinase A and G failed to reduce NaSH relaxation, while blockers of voltage-gated KV7 channels inhibited NaSH relaxation, and blockers of mitochondrial complex I and III abolished NaSH relaxation. CONCLUSION: the present findings suggest that low micromolar concentrations of free H2S by a dual mechanism opens K channels followed by lowering of smooth muscle calcium and by a mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation.
Published online October 22, 2015