Human Coronary Arteriolar Dilation to Arachidonic Acid Depends on Cytochrome P-450 Monooxygenase and Ca²⁺-Activated K⁺ Channels

From the Veterans Administration Medical Center, the Department of Internal Medicine, and Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa.

Correspondence to David D. Gutterman, MD, Medical Service (111), VA Medical Center, Iowa City, IA 52246. E-mail david-gutterman{at}uiowa.edu

Abstract—Endothelium-dependent hyperpolarization of vascular smooth muscle cells (VSMCs) plays a crucial role in regulating vascular tone, especially in resistance vessels. It has been proposed that metabolites of arachidonic acid (AA), formed by cytochrome P-450 monooxygenase (P450), are endothelium-derived hyperpolarizing factors (EDHFs). These metabolites have been reported to mediate dilation to endogenous vasoactive compounds, such as bradykinin and acetylcholine. However, it is not known whether these metabolites of AA contribute to dilation of human resistance vessels. This is important since it has been proposed that EDHF serves as a compensatory mechanism to maintain dilation in disease states. Therefore, we studied the effect of AA on vessel diameter and VSMC membrane potential in isolated human coronary microvessels. Arterioles (81±5 µm, n=70) were dissected from right atrial appendages at the time of cardiac surgery and cannulated at a distending pressure of 60 mm Hg and zero flow. Changes in internal diameter were recorded with videomicroscopy. Some vessels were impaled with glass microelectrodes to measure membrane potential of VSMCs while internal diameters were simultaneously recorded. After constriction (47±2%) with endothelin-1, AA (10^-10 to 10^-5 mol/L) induced substantial dilation of human coronary microvessels, which was abolished by removal of the endothelium. Treatment with 17-octadecynoic acid (17-ODYA, 10^-5 mol/L; a P450 inhibitor) attenuated maximal dilation to AA (49±9% versus 91±4% [control]; P<0.05 versus control), whereas indomethacin (INDO, 10^-5 mol/L; a cyclooxygenase inhibitor) and N-nitro-L-arginine methyl ester (L-NAME, 10^-4 mol/L; a NO synthase inhibitor) were without effect. Both 17-ODYA and miconazole (10^-5 mol/L, a chemically distinct P450 inhibitor) further reduced the dilation to AA in the presence of INDO. The presence of 40 mmol/L KCl or charybdotoxin (10^-8 mol/L, a blocker of large-conductance Ca²⁺-activated K⁺ channels) impaired dilation to AA (19±9% [KCl] versus 76±5% [control] and 47±6% [charybdotoxin] versus 91±3% [control]; P<0.05 for both). After depolarization with endothelin-1 (-26±1 mV from -48±3 mV [before endothelin]), AA (10^-5 mol/L) in the presence of INDO and L-NAME induced hyperpolarization of VSMCs (-57±5 mV). In the presence of 17-ODYA together with INDO and L-NAME, endothelin produced similar depolarization (-26±2 mV from – 48±3 mV), but hyperpolarization to AA was reduced (-33±2 mV; P<0.05 versus absence of 17-ODYA). AA metabolites formed primarily by P450 produce potent endothelium-dependent dilation of human coronary arterioles via opening of Ca²⁺-activated K⁺ channels and hyperpolarization of VSMCs. These findings support an important role for P450 metabolites in the regulation of human coronary arteriolar tone.

Key Words: arachidonic acid • vasodilation • coronary circulation • human • K⁺ channel

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