INTACT LUNG CYTOCHROME-P-450 IS NOT REQUIRED FOR HYPOXIC PULMONARY VASOCONSTRICTION

被引:15
作者
CHANG, SW
DUTTON, D
WANG, HL
HE, LS
STEARNS, R
HUI, A
GIACOMINI, KM
DEMONTELLANO, PO
VOELKEL, NF
机构
[1] UNIV COLORADO,HLTH SCI CTR,CARDIOVASC PULM RES LAB,DENVER,CO 80262
[2] UNIV COLORADO,HLTH SCI CTR,WEBB WARING LUNG INST,DENVER,CO 80262
[3] UNIV CALIF SAN FRANCISCO,SCH PHARM,DEPT PHARMACEUT CHEM,SAN FRANCISCO,CA 94143
来源
AMERICAN JOURNAL OF PHYSIOLOGY | 1992年 / 263卷 / 04期
关键词
SUICIDE INHIBITOR; 1-AMINOBENZOTRIAZOLE; CHLORAMPHENICOL; PERFUSED LUNGS; RAT; METYRAPONE;
D O I
10.1152/ajplung.1992.263.4.L446
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:L446 / L453
页数:8
相关论文
共 31 条
[1]   STIMULATION OF VASCULAR PROSTACYCLIN BY SKF525-A (PROADIFEN) AND RELATED-COMPOUNDS [J].
BOEYNAEMS, JM ;
DEMOLLE, D ;
VANCOEVORDEN, A .
BIOCHEMICAL PHARMACOLOGY, 1987, 36 (10) :1637-1643
[2]   ROLE OF CYTOCHROME-P-450 IN REPERFUSION INJURY OF THE RABBIT LUNG [J].
BYSANI, GK ;
KENNEDY, TP ;
KY, N ;
RAO, NV ;
BLAZE, CA ;
HOIDAL, JR .
JOURNAL OF CLINICAL INVESTIGATION, 1990, 86 (05) :1434-1441
[3]   CYTOCHROME P-450-DEPENDENT OXYGENATION OF ARACHIDONIC-ACID TO HYDROXYICOSATETRAENOIC ACIDS [J].
CAPDEVILA, J ;
MARNETT, LJ ;
CHACOS, N ;
PROUGH, RA ;
ESTABROOK, RW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1982, 79 (03) :767-770
[4]   FURTHER EVIDENCE IMPLICATING A CYTOCHROME-P-450 MEDIATED REACTION IN THE CONTRACTILE TENSION OF THE LAMB DUCTUS-ARTERIOSUS [J].
COCEANI, F ;
BREEN, CA ;
LEES, JG ;
FALCK, JR ;
OLLEY, PM .
CIRCULATION RESEARCH, 1988, 62 (03) :471-477
[5]  
CUSTER J, 1985, American Review of Respiratory Disease, V131, pA399
[6]  
DEMONTELLANO PRO, 1983, ANNU REV PHARMACOL, V23, P481
[7]   AUTOCATALYTIC ALKYLATION OF THE CYTOCHROME-P-450 PROSTHETIC HEME GROUP BY 1-AMINOBENZOTRIAZOLE - ISOLATION OF AN NN-BRIDGED BENZENE-PROTOPORPHYRIN IX ADDUCT [J].
DEMONTELLANO, PRO ;
MATHEWS, JM .
BIOCHEMICAL JOURNAL, 1981, 195 (03) :761-764
[8]   DISSOCIATION OF CYTOCHROME-P-450 INACTIVATION AND INDUCTION [J].
DEMONTELLANO, PRO ;
COSTA, AK .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1986, 251 (02) :514-524
[9]   PULMONARY VASOMOTOR RESPONSES OF ISOLATED PERFUSED CAT LUNGS TO ANOXIA [J].
DUKE, HN ;
KILLICK, EM .
JOURNAL OF PHYSIOLOGY-LONDON, 1952, 117 (03) :303-316
[10]   RELATIONSHIP BETWEEN ALVEOLAR PO2 AND THE RATE OF PARA-NITROANISOLE O-DEMETHYLATION BY THE CYTOCHROME-P-450 PATHWAY IN ISOLATED RABBIT LUNGS [J].
FISHER, AB ;
ITAKURA, N ;
DODIA, C ;
THURMAN, RG .
JOURNAL OF CLINICAL INVESTIGATION, 1979, 64 (03) :770-774