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BACKGROUND AND PURPOSE: In small arteries, small conductance Ca²⁺-activated K⁺ channels (SK (Ca) ) and intermediate conductance Ca²⁺-activated K⁺ channels (IK (Ca) ) restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI₂-independent, endothelium-derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IK (Ca) channels can be negatively regulated by PKA, we investigated whether β-adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation. EXPERIMENTAL APPROACH: Rat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell Ca²⁺i, mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording. KEY RESULTS: Intraluminal perfusion of β-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM-10 μM) without modifying the associated changes in endothelial cell Ca²⁺i. The inhibitory effect of β-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the β-adrenoceptor antagonists propranolol (non-selective), atenolol (β₁) or the PKA inhibitor KT-5720, but remained unaffected by ICI 118 551 (β₂) or glibenclamide (ATP-sensitive K⁺ channels channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by β-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IK (Ca) with 1 μM 1- (2-chlorophenyl) diphenylmethyl-1H-pyrazole (TRAM-34), but not SK (Ca) (50 nM apamin) channels prevented β-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh. CONCLUSIONS AND IMPLICATIONS: In resistance arteries, endothelial cell β₁-adrenoceptors link to inhibit endothelium-dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IK (Ca) channels and may be one consequence of raised circulating catecholamines.
Yarova et al. (Thu,) studied this question.