Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries.
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.
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom erh@farm.au.dk.
Elise R
ER
Hedegaard
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Anja
A
Gouliaev
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Anna K
AK
Winther
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Daniel D R
DD
Arcanjo
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Mathilde
M
Aalling
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Nirthika S
NS
Renaltan
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Mark E
ME
Wood
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Matthew
M
Whiteman
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Nini
N
Skovgaard
Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom.
Ulf
U
Simonsen
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D018994:Myosin Light Chains / Q000187:drug effects / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D051656:KCNQ Potassium Channels; D018994:Myosin Light Chains; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D043263:Myosin-Light-Chain Phosphatase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D002118:Calcium; D006862:Hydrogen Sulfide