Intestinal vasodilation by epoxyeicosatrienoic acids

Arachidonic acid metabolites produced by a cytochrome P450 monooxygenase

K. G. Proctor, J. R. Falck, J. Capdevila

Research output: Contribution to journalArticle

141 Citations (Scopus)

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 μg 14,15-epoxyeicosatrienoic acid/ml (14,15-EET) had no detectable effect on blood flow. However, 25 ± 3 μg 11,12-EET/ml and 36 ± 2 μg 8,9-EET/ml caused increases (134 ± 8% and 127 ± 6%) that were similar to those elicited by 8 ± 2 μg adenosine/ml (138 ± 12%). Furthermore, the increases (275 ± 38%) produced by 32 ± 6 μg 5,6-EET/ml exceeded those elicited (160 ± 10%) by a similar concentration (27 ± 3 μg/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 μg/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 μg 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.

Original languageEnglish (US)
Pages (from-to)50-59
Number of pages10
JournalCirculation Research
Volume60
Issue number1
StatePublished - 1987

Fingerprint

Mixed Function Oxygenases
Arachidonic Acid
Vasodilation
Cytochrome P-450 Enzyme System
Adenosine
Serous Membrane
Acids
Cyclooxygenase Inhibitors
Mucous Membrane
Video Microscopy
Structure-Activity Relationship
Microcirculation
Prostaglandin-Endoperoxide Synthases
Vasodilator Agents
Water

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Intestinal vasodilation by epoxyeicosatrienoic acids : Arachidonic acid metabolites produced by a cytochrome P450 monooxygenase. / Proctor, K. G.; Falck, J. R.; Capdevila, J.

In: Circulation Research, Vol. 60, No. 1, 1987, p. 50-59.

Research output: Contribution to journalArticle

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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 μg 14,15-epoxyeicosatrienoic acid/ml (14,15-EET) had no detectable effect on blood flow. However, 25 ± 3 μg 11,12-EET/ml and 36 ± 2 μg 8,9-EET/ml caused increases (134 ± 8{\%} and 127 ± 6{\%}) that were similar to those elicited by 8 ± 2 μg adenosine/ml (138 ± 12{\%}). Furthermore, the increases (275 ± 38{\%}) produced by 32 ± 6 μg 5,6-EET/ml exceeded those elicited (160 ± 10{\%}) by a similar concentration (27 ± 3 μg/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 μg/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 μg 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.",
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