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

P. L. Iarova, Sergey V. Smirnov, K. A. Dora, C J Garland

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Abstract

BACKGROUND AND PURPOSE: In small arteries, SKCa and IKCa channels restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI2 -independent, EDHF response that is the predominate endothelial mechanism for vasodilatation. As neuronal IKCa channels can be negatively regulated by PKA, we investigated whether beta-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 beta-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM - 10 muM) without modifying the associated changes in endothelial cell [Ca2+ ]i . The inhibitory effect of beta-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the beta-adrenoceptor antagonists propranolol (non-selective), atenolol (beta1 ) or the PKA inhibitor KT-5720; but remained unaffected by ICI 118,551 (beta2 ) or glibenclamide (KATP channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by beta-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IKCa (with 1 muM TRAM-34) but not SKCa (50 nM apamin) channels prevented beta-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.
CONCLUSIONS AND IMPLICATIONS: In resistance arteries, endothelial cell beta1 -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
Original languageEnglish
Pages (from-to)875-886
Number of pages12
JournalBritish Journal of Pharmacology
Volume169
Issue number4
Early online date12 Mar 2013
DOIs
Publication statusPublished - Jun 2013

Keywords

  • endothelium
  • vascular endothelium
  • potassium channels
  • endothelial cells
  • patch-clamp technique
  • resistance arteries

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