Inhibitors of cytochrome P-450 attenuate the myogenic response of dog renal arcuate arteries

K. Kauser, J. E. Clark, B. S. Masters, P. R. Ortiz de Montellano, Y. H. Ma, D. R. Harder, R. J. Roman

Research output: Contribution to journalArticlepeer-review

118 Scopus 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 μM) 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 μM) had no effect on this response. The cytochrome P-450 inhibitors ketoconazole (10 and 100 μM) and β-diethyl-aminoethyldiphenylpropylacetate (SKF 525A, 10 and 100 μM) also inhibited the myogenic response. At a pressure of 160 mm Hg, SKF 525A (10 μM) and ketoconazole (100 μM) 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 μM) and 12-hydroxy-16-heptadecynoic acid (20 μM). The thromboxane receptor antagonist SQ 29,548 (1 or 10 μM) had no effect on the pressure-induced increase in active wall tension in renal arteries. Arachidonic acid (50 μM) constricted isolated perfused renal arteries and potentiated the myogenic response in the presence of indomethacin. This response was completely reversed by ketoconazole (100 μM) or SKF 525A (100 μM). Microsomes (1 mg/ml) prepared from small renal arteries (200-500 μm) and incubated with [1-14C] arachidonic acid (0.5 μCi, 50 μM) 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 μM. 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.

Original languageEnglish (US)
Pages (from-to)1154-1163
Number of pages10
JournalCirculation research
Volume68
Issue number4
DOIs
StatePublished - 1991

Keywords

  • arachidonic acid
  • autoregulation
  • cyclooxygenase inhibitors
  • cytochrome P-450 inhibitors
  • eicosanoids
  • myogenic tone
  • renal artery
  • renal hemodynamics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Inhibitors of cytochrome P-450 attenuate the myogenic response of dog renal arcuate arteries'. Together they form a unique fingerprint.

Cite this