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Department of Pharmacology, University of Vermont Medical Research Facility, Colchester 05446, USA.

1. Vascular endothelial cells release a variety of substances which affect the membrane potential and tone of underlying vascular smooth muscle. In the presence of N omega-nitro-L-arginine to inhibit nitric oxide synthase and indomethacin to inhibit cyclo-oxygenase, acetylcholine (ACh; EC50 approximately 1 microM) elicited the release of an endothelium-derived hyperpolarizing factor (EDHF) in rabbit mesenteric arteries. 2. The hyperpolarization due to EDHF was blocked by apamin (IC50 approximately 0.3 nM), and by other inhibitors of the apamin-sensitive K+ channel (10 nM scyllatoxin, 100 microM d-tubocurarine, 300 microM gallamine) in the presence of indomethacin and N omega-nitro-L-arginine. The hyperpolarization was not blocked by glibenclamide (5 microM), iberiotoxin (10 nM), tetraethylammonium (1 mM), barium (500 microM), 4-aminopyridine (500 microM), ouabain (10 microM), bumetanide (10 microM), or nimodipine (100 nM). 3. In the presence of apamin and N omega-nitro-L-arginine, but the absence of indomethacin, ACh triggered a hyperpolarization that was blocked by glibenclamide, an inhibitor of ATP-sensitive K+ (KATP) channels. A similar glibenclamide-sensitive hyperpolarization was caused by Iloprost, a stable analogue of prostacyclin. 4. In experiments which distinguished the effects of EDHF, prostanoids and nitric oxide, hyperpolarizations and/or relaxations triggered by ACh were antagonized by muscarinic antagonists, the relative potencies (atropine approximately 4-DAMP > pirenzepine) of which indicated that the release of all three endothelium-derived factors was mediated by M3 receptors. 5. Our results suggest that ACh stimulates M3 receptors on endothelial cells, triggering the release of nitric oxide and prostanoids, which hyperpolarize underlying smooth muscle by activation of KATP channels, and the release of an EDHF, which hyperpolarizes smooth muscle through the activation of apamin-sensitive K+ (KAS) channels.

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