Cellular Mechanisms that Control Pulmonary Vascular Tone during Hypoxia and Normoxia: Possible Role of Ca2+ATPases

We investigated cellular mechanisms that may be involved in controlling cytosol calcium and pulmonary artery pressure during hypoxia and normoxia in isolated blood-perfused ferret lungs. Alveolar hypoxia in ferret lungs causes an active increase in pulmonary vascular resistance. Hypoxic pulmonary vasoconstriction directly correlates with extracellular calcium ([Ca2+]o), and the absence of [Ca2+]o in the perfusate markedly attenuates the hypoxemia-induced pulmonary vasoconstriction. Alveolar hypoxia does not potentiate the production of thromboxane B2 (TxB2) or 6-keto-PGF1α. Vanadate, a widely used inhibitor of Ca2+ATPases, increases pulmonary arterial pressure (Ppa) in the presence or absence of [Ca2+]o and without affecting the production of TxB2 or 6-keto-PGF1α. Vanadate and ouabain, an inhibitor of Na+K+ATPase, produce synergistic increases in Ppa. Amiloride, an inhibitor of Na+Ca2+ exchange, reverses the increase in Ppa caused by ouabain, but not the increase caused by vanadate. The additional effect produced by ouabain on Ppa after near maximal vanadate effect and the ability of amiloride to reverse the pulmonary vasoconstriction caused by ouabain, but not vanadate, suggests that vanadate does not inhibit Na+K+ATPase in ferret lungs. In addition, cyclic GMP (cGMP), which has been reported to increase the activity of Ca2+ATPases in vascular smooth muscle, was able to reverse and prevent the effect of vanadate on Ppa, but not the effect of ouabain. Inhibition of Ca2+ATPases with vanadate in ferret lungs increases pulmonary vascular resistance during both normoxia and hypoxia. The Ca2+ entry mediated by alveolar hypoxia appears to overpower the ability of Ca2+ATPases and other membrane Ca2+ transport proteins to translocate [Ca2+]i. Because the effects of alveolar hypoxia and vanadate on Ppa are additive and because of the strong dependence of hypoxic pulmonary vasoconstriction on [Ca2+]o, alveolar hypoxia does not appear to cause pulmonary vasoconstriction by inhibiting Ca2+ATPases. However, inhibiting Ca2+ATPases delays the recovery of Ppa from alveolar hypoxia. Agents capable of increasing cyclic AMP (cAMP) or cGMP reverse hypoxic pulmonary vasoconstriction. An increase in cGMP appears to reverse hypoxic pulmonary vasoconstriction by stimulating Ca2+ATPase-dependent Ca2+ extrusion and/or redistribution.