Hypoxic pulmonary vasoconstriction (HPV) is essential for matching lung perfusion with ventilation, thus optimizing pulmonary gas exchange. Preceding studies provided evidence for a role of both
nitric oxide (NO) and
superoxide/ H(2)O(2) formation in this vasoregulatory mechanism. Both agents might be operative via stimulation of
guanylate cyclase with formation of the vasodilatory cyclic
guanosine monophosphate (cGMP), the loss of which under conditions of
hypoxia contributes to HPV. This view is challenged by the recent suggestion of increased rather than decreased
superoxide/H(2)O(2) formation in
hypoxia. We addressed the role of NO-dependent versus NO-independent
guanylate cyclase activity in hypoxic and pharmacologically evoked vasoconstriction in perfused rabbit lungs. Two inhibitors of
soluble guanylate cyclase,
LY83583 (2 to 16 microM) and
methylene blue (20 to 60 microM), increased baseline pulmonary artery pressure under normoxic conditions and markedly amplified the
vasoconstrictor response to both
hypoxia and the stable
thromboxane analogue
U46619. Under conditions of preblocked lung NO synthesis (N(G)-mono-methyl-
L-arginine), however, additional
guanylate cyclase inhibition further enhanced the
vasoconstrictor response to
U46619 but did not influence the strength of HPV. The selective
phosphodiesterase V inhibitor
Zaprinast (1 to 10 microM), used for prolongation of the cGMP half-life, reduced the
hypoxia-induced pressor response to a larger extent than the pressor response to
U46619. This difference was lost under conditions of preblocked NO synthesis. Equilibration of the lung perfusate with molecular NO suppressed the HPV more potently than the U46619-induced
vasoconstrictor response. We conclude that NO-dependent
guanylate cyclase activity has an important role in attenuating the
vasoconstrictor response to alveolar
hypoxia in rabbit lungs. In contrast, no evidence was obtained for a role of NO-independent cGMP formation in HPV. In this feature, HPV differs from that elicited by the
thromboxane analogue
U46619.