Intact lung cytochrome P-450 is not required for hypoxic pulmonary vasoconstriction.
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.
Chang
S W
SW
Cardiovascular Pulmonary Research Laboratory, Webb-Waring Lung Institute, University of Colorado Health Sciences Center, Denver 80262.
Dutton
D
D
Wang
H L
HL
He
L S
LS
Stearns
R
R
Hui
A
A
Giacomini
K M
KM
Ortiz de Montellano
P
P
Voelkel
N F
NF
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002701:Chloramphenicol / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D004558:Electric Stimulation; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; D000804:Angiotensin II; C033020:1-aminobenzotriazole; D002701:Chloramphenicol; D003577:Cytochrome P-450 Enzyme System; D008797:Metyrapone