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ACh-induced relaxations of rabbit small mesenteric arteries: role of arachidonic acid metabolites and K⁺

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 15 March 2006 ; accepted in final form 24 February 2007

ACh-induced endothelium-dependent relaxation in rabbit small mesenteric arteries is resistant to N-nitro-L-arginine (L-NA) and indomethacin but sensitive to high K⁺, indicating the relaxations are mediated by endothelium-derived hyperpolarizing factors (EDHFs). The identity of the EDHFs in this vascular bed remains undefined. Small mesenteric arteries pretreated with L-NA and indomethacin were contracted with phenylephrine. ACh (10^–10 to 10^–6 M) caused concentration-dependent relaxations that were shifted to the right by lipoxygenase inhibition and the Ca²⁺-activated K⁺ channel inhibitors apamin (100 nM) or charybdotoxin (100 nM) and eliminated by the combination of apamin plus charybdotoxin. Relaxations to ACh were also blocked by a combination of barium (200 µM) and apamin but not barium plus charybdotoxin. Addition of K⁺ (10.9 mM final concentration) to the preconstricted arteries elicited small relaxations. K⁺ addition before ACh restored the charybdotoxin-sensitive component of relaxations to ACh. K⁺ (10.9 mM) also relaxed endothelium-denuded arteries, and the relaxations were inhibited by barium but not by charybdotoxin and apamin. With the use of whole cell patch-clamp analysis, ACh (10^–7 M) stimulated voltage-dependent outward K⁺ current from endothelial cells, which was inhibited by charybdotoxin, indicating K⁺ efflux. Arachidonic acid (10^–7 to 10^–4 M) induced concentration-related relaxations that were inhibited by apamin but not by charybdotoxin and barium. Addition of arachidonic acid after K⁺ (10.9 mM) resulted in more potent relaxations to arachidonic acid compared with control without K⁺ (5.9 mM). These findings suggest that, in rabbit mesenteric arteries, ACh-induced, L-NA- and indomethacin-resistant relaxation is mediated by endothelial cell K⁺ efflux and arachidonic acid metabolites, and a synergism exists between these two separate mechanisms.

acetylcholine; potassium channels; lipoxygenase; endothelium-derived hyperpolarizing factor

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