β1- Adrenoceptor stimulation suppresses endothelial IKCa-channel hyperpolarization and associated dilatation in resistance arteries.

Background and Purpose In small arteries, small conductance Ca2+-activated K+ channels ( SKCa) and intermediate conductance Ca2+-activated K+ channels ( IKCa) 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 IKCa 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 IKCa {with 1 μM 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole ( TRAM-34)}, but not SKCa (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 IKCa channels and may be one consequence of raised circulating catecholamines. [ABSTRACT FROM AUTHOR]