Endothelium‐dependent and BRL 34915‐induced vasodilatation in rat isolated perfused mesenteric arteries: role of G‐proteins, K+ and calcium channels

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Abstract
1 In the isolated perfused, noradrenaline (NA)-constricted mesenteric arteries of the rat, acetylcholine (0.003-1 nmol), histamine (0.01–10 nmol) and the calcium ionophore A23187 (0.01-1 nmol), caused endothelium-dependent vasodilatation while the vasodilatation by the K+ channel activator BRL 34915 (0.1-1 nmol) was independent of endothelium. 2 The guanylate cyclase inhibitor, methylene blue at 10 μm did not inhibit the action of any of the vasodilators but at 50 μm reduced the vasodilator effect of acetylcholine (ACh), histamine and A23187. 3 Infusion of ouabain or perfusion with K+-free or excess K+ (50 mm) Krebs solution reduced the vasodilator effect of ACh, histamine and A23187, suggesting the action of these agents involves, at least in part, activation of Na+/K+-ATPase. The vasodilator effect of BRL 34915 was not affected by ouabain, but abolished during perfusion with Krebs solution containing excess K+ or depleted of K+. 4 Five structurally distinct K+ channel blockers (apamin, crude scorpion venom, procaine, quinidine and tetraethylammonium) attenuated the vasodilator effect of ACh, histamine and A23187. The K+ channel blockers, except apamin and crude scorpion venom, also inhibited the vasodilatation produced by BRL 34915. 5 The vasodilator effect of ACh, histamine or A23187 was not altered in mesenteric vessels of pertussis toxin-treated rats, suggesting that the K+ channels associated with the endothelium-dependent vasodilator effect of these agents are either not coupled to G-proteins or are coupled to G-proteins that are insensitive to pertussis toxin. 6 The calcium channel blockers, diltiazem (0.1 or 1 μm), nifedipine (0.01 or 0.1 μm) or nitrendipine (1 nm) attenuated the vasodilatation produced by ACh, histamine, A23187 and also that by BRL 34915. 7 We conclude that endothelium-dependent vasodilatation induced by ACh, histamine and A23187 is mediated via activation of membrane K+ channels and Na+/K+-ATPase. The K+ channels involved in the vasodilator action of these agents are not coupled to pertussis toxin-sensitive G-proteins and appear to be regulated by Ca2+.