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Am J Physiol Lung Cell Mol Physiol 263: L446-L453, 1992;
1040-0605/92 $5.00
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AJP - Lung Cellular and Molecular Physiology, Vol 263, Issue 4 446-L453, Copyright © 1992 by American Physiological Society

ARTICLES

Intact lung cytochrome P-450 is not required for hypoxic pulmonary vasoconstriction

S. W. Chang, D. Dutton, H. L. Wang, L. S. He, R. Stearns, A. Hui, K. M. Giacomini, P. Ortiz de Montellano and N. F. Voelkel
Cardiovascular Pulmonary Research Laboratory, Webb-Waring Lung Institute, University of Colorado Health Sciences Center, Denver 80262.

Lung cytochrome P-450 has been suggested to play a role in hypoxic pulmonary vasoconstriction. We reexamined this hypothesis using specific suicide substrate inhibitors of cytochrome P-450, 1-aminobenzotriazole (1-ABT), and chloramphenicol. In isolated, blood-perfused rat lungs, 1-ABT (0.5 mg/ml) and chloramphenicol (1 mg/ml) inhibited lung microsomal cytochrome P-450 (ethoxycoumarin O-deethylase) activity to 24 and 44% of control, respectively, and blunted hypoxia and angiotensin II-induced vasoconstriction. The depression of vascular contraction by 1-ABT was not due to an effect on calcium channels, since similar concentrations of 1-ABT had no inhibitory activity on electrical field-stimulated contractile response in rabbit papillary muscle strips. However, when 1-ABT was washed out of the lung after preincubation, the vascular reactivity to hypoxia and angiotensin II was restored despite persistent depression of lung cytochrome P-450 activity to 26% of control values. In isolated rat aortic and pulmonary arterial rings, addition of 1-ABT or metyrapone to the organ bath acutely reversed norepinephrine-induced contraction but preincubation with 1-ABT, metyrapone, or chloramphenicol had no effect on subsequent norepinephrine contractions. We conclude that 1-ABT inhibited lung vascular reactivity by a mechanism independent of cytochrome P-450 inhibition or calcium channel blockade and that an intact lung cytochrome P-450 system is not required for hypoxic pulmonary vasoconstriction in rat lungs.


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