title: Contribution of glibenclamide-sensitive, ATP-dependent K+ channel activation to acetophenone analogues-mediated in vitro pulmonary artery relaxation of rat.
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 microM-1 mM) of acetophenone analogues resulted in a concentration-dependent relaxation of phenylephrine (1 microM) 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 microM N(G)-nitro-L-arginine methyl-ester) only moderately suppressed (17.6 +/- 4.2%) acetovanillone- but not paeonol- or acetophenone-mediated maximum relaxation. Glibenclamide (3 microM, an ATP-sensitive K(+) (IK(ATP)) channel blocker) markedly attenuated all acetophenone analogues-mediated endothelium-independent relaxation. Neither cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A, 10 microM), iberiotoxin (300 nM), 4-aminopyridine (3 mM), (+/-)-propranolol (1 microM, a non-selective beta-adrenoceptor blocker) nor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (3 microM, 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, IK(ATP) channels. In conclusion, our results demonstrate that acetophenone analogues caused pulmonary artery relaxation through opening of IK(ATP) channels. In addition, acetovanillone-mediated pulmonary artery relaxation is partly depended on nitric oxide released from endothelium.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, PR of China.
authors.forename: Sai Wang
authors.initials: SW
authors.lastname: Seto
authors.forename: Yick Yan
authors.initials: YY
authors.lastname: Ho
authors.forename: Hung Ngai
authors.initials: HN
authors.lastname: Hui
authors.forename: Alice Lai Shan
authors.initials: AL
authors.lastname: Au
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Kwan
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000098:Acetophenones; D015221:Potassium Channels; D009569:Nitric Oxide; C013638:paeonol; D000255:Adenosine Triphosphate; C056165:acetovanillone; C038699:acetophenone; D005905:Glyburide