Intestinal vasodilation by epoxyeicosatrienoic acids: arachidonic acid metabolites produced by a cytochrome P450 monooxygenase.

Abstract

Purified synthetic products from the cytochrome P450 pathway of arachidonate metabolism were applied to the intestinal serosa. Arteriolar blood flow was calculated using video microscopy. After a steady-state baseline, a bolus containing 10-60 micrograms 14,15-epoxyeicosatrienoic acid/ml (14,15-EET) had no detectable effect on blood flow. However, 25 +/- 3 micrograms 11,12-EET/ml and 36 +/- 2 micrograms 8,9-EET/ml caused increases (134 +/- 8% and 127 +/- 6%) that were similar to those elicited by 8 +/- 2 micrograms adenosine/ml (138 +/- 12%). Furthermore, the increases (275 +/- 38%) produced by 32 +/- 6 micrograms 5,6-EET/ml exceeded those elicited (160 +/- 10%) by a similar concentration (27 +/- 3 micrograms/ml) of adenosine. Thus, a structure-activity relationship is suggested. Nevertheless, these values probably underestimate the potency of the EETs because the vasoactivity was reduced by contact with water. The activity of the cyclooxygenase pathway seemed to limit the formation of vasoactive quantities of EETs, or other nonprostanoids, from exogenous arachidonate in the serosa but not the mucosa. A bolus (1.3 +/- 0.2 mg/ml) or continuous application (122 +/- 45 micrograms/ml) of arachidonate caused blood flow increases (236 +/- 14% or 229 +/- 27%) that were almost eliminated (129 +/- 5% or 121 +/- 9%) by a cyclooxygenase inhibitor; the residual response was abolished by a cytochrome P450 inhibitor. However, cytochrome P450 inhibitors alone did not attenuate the arachidonate response. In contrast, a continuous application of 194 micrograms arachidonate/ml to the mucosa caused a markedly smaller blood flow increase (119 +/- 8%) and cyclooxygenase inhibitors potentiated (132 +/- 8%), rather than reduced, this response. We conclude that EETs are a labile class of vasodilators with a potency comparable to adenosine in the intestinal microcirculation. Indirect evidence suggests regional differences in the formation of vasoactive quantities of arachidonate metabolites within the intestinal wall.

Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

“…23 Furthermore, in vitro studies revealed that incubation of endothelial cells with clofibrate for 72 hours causes membrane hyperpolarization, an effect attributed to EET formation. 24 EETs induce vasodilation in the mesenteric vasculature 25 and also have been identified as EDHF-like in certain vascular beds. 12 Hence, enhancing EET formation could cause vasodilation, reduced blood pressure and increased EDHF activity.…”

The rabbit pulmonary cytochrome P450 arachidonic acid metabolic pathway: characterization and significance.

“…The P450-derived arachidonic acid metabolites have numerous biological activities, including effects on vascular tissues (7)(8)(9)(10), modulation of membrane ion fluxes (11)(12)(13), stimulation of peptide hormone release ( 14,15), inhibition of cyclooxygenase activity and platelet aggregation ( 16), angiogenic effects (17), and effects on neutrophil chemotaxis ( 18 ). McGiff ( 11) has recently proposed that the renal arachidonic acid monooxygenase is involved in the pathophysiology of hypertension.…”

Metabolism of arachidonic acid by the cytochrome P450 enzyme in patients with chronic Keshan disease and dilated cardiomyopathy

“…Arachidonic acid (AA) is oxidized through three major metabolic pathways: Cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYPs) (4 (5). According to the CYP metabolic pathway followed by AA, the major metabolites are either epoxyeicosatrienoic acids (EETs) or 20-hydroxyeicosatetraenoic acids (20-HETE), which are primarily vasodilators or vasoconstrictors, respectively (6).…”