Contribution of glibenclamide-sensitive, ATP-dependent K+ channel activation to acetophenone analogues-mediated in vitro pulmonary artery relaxation of rat

Seto, Sai Wang, Ho, Yick Yan, Hui, Hung Ngai, Au, Alice Lai Shan, and Kwan, Yiu Wa (2006) Contribution of glibenclamide-sensitive, ATP-dependent K+ channel activation to acetophenone analogues-mediated in vitro pulmonary artery relaxation of rat. Life Sciences, 78 (6). pp. 631-639.

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Abstract

Compared to the currently available therapeutic drugs for peripheral vascular diseases, agents that are selective for relaxing pulmonary circulation are scarce. The present study was undertaken, using isometric tension change measurement and whole-cell patch-clamp electrophysiology methods, to evaluate the vascular relaxation effect and the underlying mechanisms involved of two naturally found alkaloids: paeonol (2-hydroxy-4-methoxy-acetophenone), acetovanillone (4-hydroxy-3-methoxy-acetophenone) and the non-substituted analogue acetophenone on pulmonary artery of Sprague-Dawley rats. Cumulative administration (3 μM–1 mM) of acetophenone analogues resulted in a concentration-dependent relaxation of phenylephrine (1 μM) pre-contracted pulmonary artery. A relative order of inhibitory potency, estimated by comparing the concentration at which a 50% relaxation of phenylephrine-induced contraction observed was: acetovanillone > paeonol > acetophenone. Endothelial denudation and inhibition of nitric oxide synthase (with 20 μM NG-nitro-l-arginine methyl-ester) only moderately suppressed (17.6 ± 4.2%) acetovanillone- but not paeonol- or acetophenone-mediated maximum relaxation. Glibenclamide (3 μM, an ATP-sensitive K+ (IKATP) channel blocker) markedly attenuated all acetophenone analogues-mediated endothelium-independent relaxation. Neither cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A, 10 μM), iberiotoxin (300 nM), 4-aminopyridine (3 mM), (±)-propranolol (1 μM, a non-selective β-adrenoceptor blocker) nor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (3 μM, a guanylate cyclase inhibitor) altered endothelium-independent relaxation. In electrophysiological experiments using single pulmonary artery smooth muscle cells, acetovanillone, paeonol, acetophenone and cromakalim activated glibenclamide-sensitive, IKATP channels. In conclusion, our results demonstrate that acetophenone analogues caused pulmonary artery relaxation through opening of IKATP channels. In addition, acetovanillone-mediated pulmonary artery relaxation is partly depended on nitric oxide released from endothelium.

Item ID: 17638
Item Type: Article (Research - C1)
ISSN: 1879-0631
Keywords: acetophenone; rat; pulmonary artery relaxation; glibenclamide-sensitive; ATP-dependent K+ channel
Date Deposited: 21 Aug 2013 06:43
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology @ 100%
SEO Codes: 92 HEALTH > 9299 Other Health > 929999 Health not elsewhere classified @ 100%
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