Hypoxic pulmonary vasoconstriction in conscious sheep. Role of mast cell degranulation

We used pharmacologic and histologic techniques to investigate the role of mast cells in the mediation of hypoxic pulmonary vasoconstriction in conscious sheep. Breathing a hypoxic gas mixture (13% O₂, 87% nitrogen) caused hypoxic pulmonary vasoconstriction (HPV) with increases in mean pulmonary artery pressure and pulmonary vascular resistance by 97 and 90%, respectively. Intravenous pretreatment with the mast cell membrane stabilizing agent cromolyn sodium (3 mg/kg/min) completely blocked HPV, whereas the H₁-histamine receptor antagonist chlorpheniramine, alone or in combination with the H₂-receptor antagonist metiamide and the prostaglandin synthetase inhibitor indomethacin, failed to prevent HVP. Cromolyn sodium failed to modify the pulmonary pressor response to infusions of norepinephrine (alpha-agonist), tyramine (catecholamine-releasing agent), and histamine, indicating the specificity of cromolyn sodium action on the mast cells. Electromicroscopic studies of pulmonary perivascular mast cells showed that a 90-min exposure to the hypoxic gas mixture reduced the total number of granules per mast cell to 75% of control. This was blocked by cromolyn sodium pretreatment. We conclude that in conscious sheep, HPV is initiated by the liberation of a mast cell product (other than histamine) that either directly or indirectly causes pulmonary vasoconstriction.