Published Online
on June 2, 2005

A more recent version of this article appeared on July 1, 2005

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Submitted on January 30, 2005
Revised on February 18, 2005
Accepted on February 23, 2005

Possible Role for K⁺ in Endothelium-Derived Hyperpolarizing Factor-Linked Dilatation in Rat Middle Cerebral Artery

Alister J. McNeish PhD; Kim A. Dora PhD; and Christopher J. Garland PhD^*

From the Department of Pharmacy and Pharmacology, the University of Bath, Claverton Down, United Kingdom.

^* To whom correspondence should be addressed. E-mail: c.j.garland{at}bath.ac.uk.

Background and Purpose--Endothelium-derived hyperpolarizing factor (EDHF) and K⁺ are vasodilators in the cerebral circulation. Recently, K⁺ has been suggested to contribute to EDHF-mediated responses in peripheral vessels. The EDHF response to the protease-activated receptor 2 ligand SLIGRL was characterized in cerebral arteries and used to assess whether K⁺ contributes as an EDHF.

Methods--Rat middle cerebral arteries were mounted in either a wire or pressure myograph. Concentration-response curves to SLIGRL and K⁺ were constructed in the presence and absence of a variety of blocking agents. In some experiments, changes in tension and smooth muscle cell membrane potential were recorded simultaneously.

Results--SLIGRL (0.02 to 20 µmol/L) stimulated concentration and endothelium-dependent relaxation. In the presence of N^G-nitro-L-arginine methyl ester, relaxation to SLIGRL was associated with hyperpolarization and sensitivity to a specific inhibitor of IK_Ca, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (1µmol/L), reflecting activation of EDHF. Combined inhibition of K_IR with Ba²⁺ (30µmol/L) and Na⁺/K⁺-ATPase with ouabain (1 µmol/L) markedly attenuated the relaxation to EDHF. Raising extracellular [K⁺] to 15 mmol/L also stimulated smooth muscle relaxation and hyperpolarization, which was also attenuated by combined application of Ba²⁺ and ouabain.

Conclusions--SLIGRL evokes EDHF-mediated relaxation in the rat middle cerebral artery, underpinned by hyperpolarization of the smooth muscle. The profile of blockade of EDHF-mediated hyperpolarization and relaxation supports a pivotal role for IK_Ca channels. Furthermore, similar inhibition of responses to EDHF and exogenous K⁺ with Ba²⁺ and ouabain suggests that K⁺ may contribute as an EDHF in the middle cerebral artery.

Key words: endothelium • endothelium-dependent hyperpolarization factor • PAR-2 receptor • potassium channels

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