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

• Published in: British journal of pharmacology 2013-05, Vol.169 (4), p.875-886
• Main Authors: Yarova, PL, Smirnov, SV, Dora, KA, Garland, CJ
• Format: Article
• Language: English
• Subjects: acetylcholine; adrenergic (ant)agonists; endothelial receptors; PKA; Research Papers; β‐adrenoceptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12160

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.