β 1 ‐ A drenoceptor stimulation suppresses endothelial IK Ca ‐channel hyperpolarization and associated dilatation in resistance arteries

• Published in: British journal of pharmacology Vol. 169; no. 4; pp. 875 - 886
• Main Authors: Yarova, PL, Smirnov, SV, Dora, KA, Garland, CJ
• Format: Journal Article
• Language: English
• Published: 01.06.2013
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12160

Background and Purpose In small arteries, small conductance Ca 2+ ‐activated K + channels ( SK Ca ) and intermediate conductance Ca 2+ ‐activated K + channels ( IK Ca ) restricted to the vascular endothelium generate hyperpolarization that underpins the NO ‐ and PGI 2 ‐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 [ Ca 2+ ] 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  μ M) without modifying the associated changes in endothelial cell [ Ca 2+ ] 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 ( β 1 ) or the PKA inhibitor KT ‐5720, but remained unaffected by ICI 118 551 ( β 2 ) 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  μ M 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 β 1 ‐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.