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(Stroke. 2005;36:1526.)
© 2005 American Heart Association, Inc.

Original Contributions

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

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

Correspondence to Christopher J. Garland, Department of Pharmacy and Pharmacology, the University of Bath, Claverton Down, Bath, BA2 7AY, UK. 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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