Cytochrome P₄₅₀ monooxygenase mediates arachidonic acid induced coronary microcirculation dilation in dogs

We recently showed that cytochrome P₄₅₀ (P₄₅₀) contributes importantly to canine coronary microvascular dilatation in vivo. P₄₅₀ metabolizes arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs), which our laboratory has shown are potent dilators of coronary microvessels. We, therefore, tested the hypothesis that AA-induced coronary microvascular dilation is mediated in part through a P₄₅₀ pathway. Adult mongrel dogs (n=22) of either sex were anesthetized. A thoracotomy was performed and coronary arterioles (<100 μm) were observed using stroboscopic epi-illumination during the topical application of AA (1, 5, 10 μM) Coronary microvascular responses were examined in the presence of indomethacin (Indo, 5 mg/kg iv) and Indo plus clotrimazole (CLO, 1.8 μM topically, a cytochrome P₄₅₀ monooxygenase inhibitor). Results (mean ± SEM, *p<0.05 vs baseline). AA (μM. topically) 1 5 10 Baseline 14 ± 4 35 ± 3 61 ± 5 Indo + CLO 9 ± 3 29 ± 3 48 ± 2* Indo alone did not alter AA-induced dilatation. However, Indo+CLO attenuated AA-induced dilatation, whereas responses to nitroprusside were unaffected. These results suggest that AA induced coronary microvascular dilation is mediated in part by a cytochrome P₄₅₀ pathway.