1. Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries.
- Author
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Hedegaard ER, Gouliaev A, Winther AK, Arcanjo DD, Aalling M, Renaltan NS, Wood ME, Whiteman M, Skovgaard N, and Simonsen U
- Subjects
- Animals, Electron Transport Complex I drug effects, Electron Transport Complex III antagonists & inhibitors, Hydrogen Sulfide metabolism, In Vitro Techniques, KCNQ Potassium Channels drug effects, Mesenteric Arteries metabolism, Muscle, Smooth, Vascular metabolism, Myosin Light Chains drug effects, Myosin Light Chains metabolism, Myosin-Light-Chain Phosphatase antagonists & inhibitors, Phosphorylation, Potassium Channel Blockers pharmacology, Protein Kinase Inhibitors pharmacology, Rats, Rats, Wistar, Vasodilation drug effects, Calcium metabolism, Hydrogen Sulfide pharmacology, Mesenteric Arteries drug effects, Muscle Relaxation drug effects, Muscle, Smooth, Vascular drug effects, Potassium Channels drug effects
- Abstract
Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (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 sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] 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 NaHS 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 NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2016
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