Cytochrome P-450 pathway in acetylcholine-induced canine coronary microvascular vasodilation in vivo

Mark D. Widmann, Neal L. Weintraub, Jonathan L. Fudge, Leonard A. Brooks, Kevin C. Dellsperger

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In the canine coronary microcirculation, acetylcholine (ACh)-induced vasodilation of large (≥100 μm) epicardial arterioles (LgA), but not small (<100 μm) epicardial arterioles (SmA), is blocked by nitric oxide (NO) synthase inhibitors in vivo. We hypothesized that the ACh-induced vasodilation of SmA is mediated by a cytochrome P-450 metabolite of arachidonic acid (AA). Epicardial coronary microvascular diameters in dogs were measured at baseline and after treatment with topically applied ACh (1, 10, and 100 μM), AA (1, 5, and 10 μM), or sodium nitroprusside (SNP; 10-100 μM). Coronary microvascular diameters were compared among control dogs (group OO); dogs pretreated with Nω-nitro-L-arginine (L-NNA; 70 μM topically) (group NO)); dogs pretreated with L-NNA plus clotrimazole (Clo; 1.6 μM topically) or 17-octadecynoic acid (ODYA; 2 μM topically), cytochrome P-450 monooxygenase inhibitors (groups NC and NY, respectively); dogs pretreated with Clo alone (group OC); and dogs pretreated with L-NNA plus Clo with AA as the agonist (group AA). ACh-induced vasodilation of LgA was abolished by L-NNA alone, whereas in SmA, L-NNA was without effect. Clo alone did not inhibit ACh-induced dilation in either SmA or LgA. However, the combinations of L-NNA plus either Clo or ODYA abolished ACh- and AA-induced dilation of SmA (100 μM ACh: NC, 3 ± 5%; NY, 8 ± 2%; 10 μM AA: 6 ± 3%) but did not affect responses to SNP. These results suggest that the ACh-induced vasodilation of SmA is mediated in part by cytochrome P-450 metabolites of AA and provide the first evidence that the cytochrome P-450 pathway contributes to the regulation of coronary resistance vessels in vivo.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number1 43-1
StatePublished - Jan 1 1998



  • Arachidonic acid
  • Arginine analog
  • Clotrimazole
  • Endothelium-derived hyperpolarizing factor
  • Intravital microscopy

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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