Nitric oxide (NO)-dependent but not NO-independent guanylate cyclase activation attenuates hypoxic vasoconstriction in rabbit lungs

Hypoxic pulmonary vasoconstriction (HPV) is essential for matching lung per fusion with ventilation, thus optimizing pulmonary gas exchange. Preceding studies provided evidence for a role of both nitric oxide (NO) and superoxi de/H2O2 formation in this vasoregulatory mechanism. Both agents might be op erative via stimulation of guanylate cyclase with formation of the vasodila tory cyclic guanosine monophosphate (cGMP), the loss of which under conditi ons of hypoxia contributes to HPV. This view is challenged by the recent su ggestion of increased rather than decreased superoxide/H2O2 formation in hy poxia, We addressed the role of NO-dependent versus NO-independent guanylat e cyclase activity in hypoxic and pharmacologically evoked vasoconstriction in perfused rabbit lungs. Two inhibitors of soluble guanylate cyclase, LY8 3583 (2 to 16 mu M) and methylene blue (20 to 60 mu M), increased baseline pulmonary artery pressure under normoxic conditions and markedly amplified the vasoconstrictor response to both hypoxia and the stable thromboxane ana logue U46619, Under conditions of preblocked lung NO synthesis (Nc-monometh yl-L-arginine), however, additional guanylate cyclase inhibition further en hanced the vasoconstrictor response to U46619 but did not influence the str ength of HPV. The selective phosphodiesterase V inhibitor Zaprinast (1 to 1 0 mu M), used for prolongation of the cGMP half-life, reduced the hypoxia-i nduced presser response to a larger extent than the presser response to U46 619. This difference was lost under conditions of preblocked NO synthesis. Equilibration of the lung perfusate with molecular NO suppressed the HPV mo re potently than the U46619-induced vasoconstrictor response. We conclude t hat NO-dependent guanylate cyclase activity has an important role in attenu ating the vasoconstrictor response to alveolar hypoxia in rabbit lungs. In contrast, no evidence was obtained for a role of NO-independent cGMP format ion in HPV. In this feature, HPV differs from that elicited by the thrombox ane analogue U46619.