Faculty Collaboration Database

Inhibitors of cytochrome P-450 attenuate the myogenic response of dog renal arcuate arteries. Circ Res 1991 Apr;68(4):1154-63

Date

04/01/1991

Pubmed ID

1901255

DOI

10.1161/01.res.68.4.1154

Scopus ID

2-s2.0-0025967421 (requires institutional sign-in at Scopus site)   134 Citations

Abstract

The role of cytochrome P-450 in the myogenic response of isolated, perfused renal arcuate arteries of dogs to elevations in transmural pressure was examined. The phospholipase A2 inhibitor oleyloxyethylphosphorylcholine (1 and 10 microM) inhibited the greater than threefold increase in active wall tension in these arteries after an elevation in perfusion pressure from 80 to 160 mm Hg. Inhibition of cyclooxygenase activity with indomethacin (1 or 10 microM) had no effect on this response. The cytochrome P-450 inhibitors ketoconazole (10 and 100 microM) and beta-diethyl-aminoethyldiphenylpropylacetate (SKF 525A, 10 and 100 microM) also inhibited the myogenic response. At a pressure of 160 mm Hg, SKF 525A (10 microM) and ketoconazole (100 microM) reduced active wall tension in renal arteries by approximately 70%. Partial inhibition of the myogenic response was obtained after perfusion of the vessels with mechanism-based inhibitors of P-450, 1-aminobenzotriazole (75 microM) and 12-hydroxy-16-heptadecynoic acid (20 microM). The thromboxane receptor antagonist SQ 29,548 (1 or 10 microM) had no effect on the pressure-induced increase in active wall tension in renal arteries. Arachidonic acid (50 microM) constricted isolated perfused renal arteries and potentiated the myogenic response in the presence of indomethacin. This response was completely reversed by ketoconazole (100 microM) or SKF 525A (100 microM). Microsomes (1 mg/ml) prepared from small renal arteries (200-500 microns) and incubated with [1-14C]arachidonic acid (0.5 mu Ci, 50 microM) produced a metabolite that coeluted with 20-hydroxyeicosatetraenoic acid (20-HETE) during reversed-phase high-performance liquid chromatography. The formation of this product was inhibited by both ketoconazole and SKF 525A at concentrations of 10 and 100 microM. These results are consistent with the involvement of the vasoconstrictor 20-HETE and other cytochrome P-450 metabolites of endogenous fatty acids in the myogenic response.

Author List

Kauser K, Clark JE, Masters BS, Ortiz de Montellano PR, Ma YH, Harder DR, Roman RJ

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Bridged Bicyclo Compounds, Heterocyclic
Cyclooxygenase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Dogs
Fatty Acids, Monounsaturated
Fatty Acids, Unsaturated
Hydrazines
Indomethacin
Ketoconazole
Kinetics
Muscle, Smooth, Vascular
Phospholipases A
Phospholipases A2
Phosphorylcholine
Proadifen
Renal Artery
Triazoles