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The Contribution of d-Tubocurarine–sensitive and Apamin-sensitive K-channels to EDHF-mediated Relaxation of Mesenteric Arteries From eNOS−/− Mice

Chen, Xiaoliang MD*; Li, Yang PhD; Hollenberg, Morley MD; Triggle, Chris R. PhD; Ding, Hong PhD

Journal of Cardiovascular Pharmacology: May 2012 - Volume 59 - Issue 5 - p 413–425
doi: 10.1097/FJC.0b013e318248acd9
Original Article

Abstract: The nature of the potassium channels involved in determining endothelium-derived hyperpolarizing factor–mediated relaxation was investigated in first-order small mesenteric arteries from male endothelial nitric oxide synthase (eNOS−/−)–knockout and control (+/+) mice. Acetylcholine-induced endothelium-dependent relaxation of small mesenteric arteries of eNOS−/− was resistant to Nω-nitro-L-arginine and indomethacin and the guanylyl cyclase inhibitor, 1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one. Apamin and the combination of apamin and iberiotoxin or apamin and charybdotoxin induced a transient endothelium-dependent contraction of small mesenteric arteries from both eNOS−/− and +/+ mice. Acetylcholine-induced relaxation in eNOS−/− mice was unaffected by charybdotoxin or apamin alone but significantly inhibited by the combination of these agents. However, the combination of scyllatoxin and iberiotoxin did not mimic the inhibitory effect of the apamin/charybdotoxin combination. Tubocurarine alone completely blocked acetylcholine-induced relaxation in eNOS−/− mice. Single channel analysis of myocytes from small mesenteric arterioles revealed a large conductance calcium-activated potassium channel that was sensitive to iberiotoxin, charybdotoxin, and tetraethylammonium. Tubocurarine blocked this channel from the cytosolic side but not when applied extracellularly. Solutions of nitric oxide (NO) gas also relaxed small mesenteric arteries that had been contracted with cirazoline in a concentration-dependent manner, and the sensitivity to NO was reduced by iberiotoxin and the combination of apamin, scyllatoxin, or tubocurarine with charybdotoxin but not by apamin, charybdotoxin, scyllatoxin, or tubocurarine alone. These data indicate that acetylcholine-induced endothelium-derived hyperpolarizing factor–mediated relaxation in small mesenteric arteries from eNOS−/− involved the activation of tubocurarine and apamin-/charybdotoxin-sensitive K-channels. In eNOS+/+ mice, the acetylcholine-induced response was primarily mediated by NO and was sensitive to iberiotoxin and the combination of apamin and charybdotoxin.

*Department of Cadre & Cardiology, The Second Hospital of Hangzhou, Hangzhou Normal University, Hangzhou, China

Department of Physiology and Pharmacology, Faculty of Medicine, The University of Calgary, Calgary, Canada

Department of Pharmacology, Medical Education, Weill Cornell Medical College in Qatar, Doha, Qatar.

Reprints: Hong Ding, PhD, Department of Pharmacology, Medical Education, Weill Cornell Medical College in Qatar, Doha, Qatar (e-mail:

Partially supported by the National Priorities Research Program's grant (08-165-3-054) from the Qatar Foundation and also a grant from the Canadian Institutes of Health Research (HD, CRT, and MH and MH and CRT, respectively).

The authors report no conflicts of interest.

Received July 21, 2011

Accepted December 28, 2011

© 2012 Lippincott Williams & Wilkins, Inc.