Evidence for Involvement of Both IK Ca and SK Ca Channels in Hyperpolarizing Responses of the Rat Middle Cerebral Artery

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Abstract
Background and Purpose— Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IK Ca channels alone, contrasting with peripheral vessels where block of both IK Ca and SK Ca is required. As the contribution of IK Ca and SK Ca to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SK Ca might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions. Methods— Rat middle cerebral arteries (≈175 μm) were mounted in a wire myograph. The effect of K Ca channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 μmol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial K Ca channels revealed with immunohistochemistry. Results— SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IK Ca (TRAM-34, 1 μmol/L) or SK Ca (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SK Ca and IK Ca within the endothelium. Conclusions— In the absence of NO, IK Ca underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SK Ca contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SK Ca expression may be altered.

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