Evidence for cGMP mediation of skeletal muscle arteriolar dilation to lactate.
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.
Chen
Y L
YL
Department of Physiology, New York Medical College, Valhalla 10595, USA.
Wolin
M S
MS
Messina
E J
EJ
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*
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