Role of cytochrome P-450 in alveolar hypoxic pulmonary vasoconstriction in dogs.
Alveolar hypoxia induces pulmonary vasoconstriction by an unknown mechanism. Cytochrome P-450 (C-P450) is found in the lung and may modify pulmonary vascular tone via its sensitivity to changes in oxygen tension or by affecting metabolism of a chemical mediator. Metyrapone and carbon monoxide are both inhibitors of C-P450. We tested alveolar hypoxic pulmonary vasoconstriction (AHPV) in 20 dogs before, during, and after separate administration of each inhibitor. Anesthetized dogs were ventilated through a double lumen endotracheal tube allowing ventilation of one lung with N(2) or CO as a hypoxic challenge and ventilation of the other lung with O(2) to maintain adequate systemic oxygenation. Distribution of lung perfusion was determined with intravenous (133)Xenon and external chest detectors. Before infusion of metyrapone, mean perfusion to the test lung decreased 30% with alveolar hypoxic challenge, but decreased only 10% during metyrapone infusion and returned to a base-line mean decrease of 31% after completion of metyrapone infusion. Prostaglandin F(2) alpha and angiotensin II infusions produced equivalent increases in pulmonary vascular resistance before and during metyrapone infusion. Before CO, mean test lung perfusion decreased 31% with alveolar hypoxia but was reduced only 10% from control when unilateral end-tidal CO% was >75%. Washout of alveolar CO with unilateral N(2) ventilation restored AHPV, with perfusion decreasing 29% from control. Thus, both metyrapone and carbon monoxide can reversibly inhibit AHPV. C-P450 may, therefore, be involved in the transduction process of the vasoconstrictor response to alveolar hypoxia.
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology; D002302:Cardiac Output / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004285:Dogs; D000860:Hypoxia / Q000201:enzymology / Q000503:physiopathology*; D008797:Metyrapone / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology; D011651:Pulmonary Artery / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D011460:Prostaglandins F; D000804:Angiotensin II; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D008797:Metyrapone