title: Evidence for cGMP mediation of skeletal muscle arteriolar dilation to lactate.
abstract: In this study we tested the hypothesis that lactate, independent of changes in pH, can affect skeletal muscle blood flow through arteriolar dilation that may be mediated by guanosine 3',5'-cyclic monophosphate. Isolated, cannulated, and pressurized first-order rat cremaster skeletal muscle arterioles were studied in a chamber containing Krebs-bicarbonate buffer under no-flow conditions. At pH 7.4 and PO2 of 65 Torr, neutralized lactic acid (lactate) and pyruvic acid (pyruvate) caused arteriolar dilation over the 1-10 mM concentration range. This response to lactate was not altered by 10(-5) M indomethacin, 10(-4) M NG-nitro-L-arginine, or removal of the endothelium. However, responses to 1 and 3 mM pyruvate were significantly inhibited by 100% by endothelium removal, and the response to 10 mM pyruvate was inhibited by 71%. The relaxation of endothelium-denuded arterioles to lactate was inhibited by 10 microM methylene blue, 10 microM LY-83583, hypoxia (PO2 7-10 Torr), and diphenyliodonium, an inhibitor of superoxide-producing flavo-protein enzymes. In contrast, arteriolar dilation to the acidification of the Krebs buffer to pH 7.15, produced by increasing the CO2 concentration of the gas mixture from 5 to 10%, was not inhibited by methylene blue. These results are consistent with lactate-induced skeletal muscle arteriolar dilation being dependent on H2O2-mediated activation of vascular smooth muscle guanylate cyclase and independent of endothelium-derived mediators.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla 10595, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: M S
authors.initials: MS
authors.lastname: Wolin
authors.forename: E J
authors.initials: EJ
authors.lastname: Messina
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000033:anatomy & histology / Q000502:physiology; D002417:Cattle; D006152:Cyclic GMP / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006861:Hydrogen Peroxide; D006863:Hydrogen-Ion Concentration; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply; D011651:Pulmonary Artery / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000502:physiology; D014664:Vasodilation / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019344:Lactic Acid; C041715:6-anilino-5,8-quinolinedione; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue; D007213:Indomethacin