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(Circulation Research. 2005;96:376.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Epoxyeicosatrienoic Acids Are Released to Mediate Shear Stress–Dependent Hyperpolarization of Arteriolar Smooth Muscle

An Huang, Dong Sun, Azita Jacobson, Mairead A. Carroll, John R. Falck, Gabor Kaley

From the Departments of Physiology (A.H., D.S., A.J., G.K.) and Pharmacology (M.A.C.), New York Medical College, Valhalla; and the Department of Biochemistry (J.R.F.), University of Texas, Southwestern Medical Center, Dallas.

Correspondence to An Huang, MD, PhD, Department of Physiology, New York Medical College Valhalla, NY 10595. E-mail an_huang{at}nymc.edu

We hypothesized that shear stress stimulates the release of epoxyeicosatrienoic acids (EETs) from arteriolar endothelium, which directly hyperpolarize smooth muscle. To test this hypothesis, a perfusion system, consisting of two separate, serially connected chambers (A and B), was used. A donor vessel, isolated from gracilis muscle of female NO-deficient mice and rats, was cannulated in chamber A. In chamber B, an endothelium-denuded detector vessel isolated from mesentery of these animals was cannulated. In the presence of indomethacin, 5, 10, and 20 dyne/cm² shear stress elicited dilation of donor vessels, followed by dilation of detector vessels. Changes in membrane potential of the detector vessel smooth muscle cells in response to the perfusate from 5 and 10 dyne/cm² shear stress–stimulated donor vessels was also recorded (by –12 to –15 and –20 to –30 mV, respectively). Exposing detector vessels to 30 mmol/L KCl or pretreating them with iberiotoxin abolished their hyperpolarization and dilation to the flow of perfusate. Pretreatment of donor vessels with PPOH, an inhibitor of cytochrome P-450/epoxygenase, eliminated dilator responses in both donor and detector vessels, as well as the hyperpolarization of detector vessels. GC-MS analysis showed increasing release of EETs into the perfusate collected from 1, 5, and 10 dyne/cm² shear stress–stimulated arterioles, which was abolished by PPOH. Thus, EETs, released from endothelial cells of donor vessels stimulated with shear stress, hyperpolarize smooth muscle of downstream detector vessels, confirming their identity as endothelium-derived hyperpolarizing factors and suggesting that gap junctional communication may not be necessary for shear stress–stimulated EDHF-mediated vasodilation.

Key Words: NO deficiency • shear stress • EET • hyperpolarization • arterioles

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