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

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Abstract
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]-1 H -pyrazole (1μmol/L), reflecting activation of EDHF. Combined inhibition of K IR with Ba 2+ (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 Ba 2+ 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 Ba 2+ and ouabain suggests that K + may contribute as an EDHF in the middle cerebral artery.