Hydrogen peroxide-induced pulmonary vasodilation: role of guanosine 3',5'-cyclic monophosphate.
Hydrogen peroxide (H2O2), but not tertbutyl hydroperoxide, produces a concentration-dependent vasodilation of the pulmonary circulation in isolated saline perfused rabbit lungs when pulmonary arterial pressures (PAP) are raised with the thromboxane analogue U-46619. This vasodilation was enhanced in the presence of indomethacin, suggesting that H2O2 possesses both a prostaglandin-mediated constrictor and an additional dilator mechanism. In isolated rabbit intrapulmonary arteries the endothelium did not alter the dose-dependent relaxation of arterial rings to H2O2, and indomethacin enhanced the relaxant response of the peroxide. The decrease in PAP and relaxation of isolated pulmonary arteries observed with H2O2 was attenuated with 10 microM methylene blue, an inhibitor of soluble guanylate cyclase activation. M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase inhibitor, enhanced the vasodilation or relaxation to the peroxide in both preparations. These changes were not endothelium dependent. Inhibition of the cGMP-associated endothelium-derived relaxant factor (EDRF) with nitro-L-arginine, did not alter relaxation of arterial rings to peroxide. Thus H2O2 appears to produce pulmonary vasodilation through the activation of guanylate cyclase and accumulation of cGMP. Both H2O2 and EDRF may function as tonic stimulators of guanylate cyclase in the pulmonary circulation and contribute to the maintenance of low basal pressures.
Burke-Wolin
T
T
Department of Medicine, New York Medical College, Valhalla 10595.
Abate
C J
CJ
Wolin
M S
MS
Gurtner
G H
GH
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D010477:Perfusion; D011453:Prostaglandins / Q000502:physiology; D011817:Rabbits; D014664:Vasodilation / Q000502:physiology*
D011453:Prostaglandins; D006861:Hydrogen Peroxide; D006152:Cyclic GMP; D007213:Indomethacin