O2-dependent modulation of calf pulmonary artery tone by lactate: potential role of H2O2 and cGMP

Lactate was found to produce a relaxation of isolated endothelium-removed calf pulmonary arteries precontracted with 20-30 mM K+. Examination of the mechanism of this response indicates that it appears to be O2 dependent and mediated via guanosine 3',5'-cyclic monophosphate (cGMP), since it is reduced by hypoxia (N2 atmosphere, PO2 = 8-10 Torr) and because the relaxation was both eliminated by inhibition of soluble guanylate cyclase activation with methylene blue and enhanced by an antagonist of cGMP-selective phosphodiesterases (M & B 22948). Relaxation to lactate is not mediated via prostaglandin formation or arginine-derived nitric oxide, since indomethacin or nitro-L-arginine, respectively, did not alter the response. Lucigenin-elicited chemiluminescence, a potential detector of superoxide anion, was significantly increased by lactate only after inhibition of Cu-Zn-superoxide dismutase (via pretreatment with diethyldithiocarbamate). Pyruvate (5 mM) produced only minimal relaxation and did not significantly increase chemiluminescence. In the homogenate fraction of the arterial smooth muscle, NAD plus lactate or NADH was required to observe increased chemiluminescence. The calf pulmonary arterial smooth muscle contraction to hypoxia and relaxation to posthypoxic reoxygenation was observed to be increased by lactate, associated with a reduced level tone generation under O2 but not N2 atmosphere. Thus lactate, but not pyruvate, appears to cause a cGMP-mediated relaxation in the calf pulmonary artery through an increased intracellular H2O2 generation via the NADH-dependent production of superoxide anion, and activation of this relaxing mechanism modulates O2-elicited tone responses.