Characterization of muscarinic receptorsmediating vasodilation in rat perfused kidney

Abstract

The muscarinic receptor mediating vasolidation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10 −7 M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasolidation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (R)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester (R)-aceclidine = (S)-nipocotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M 3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol ∼ hexahydro-sila-difenol > pirenzepine ∼ p-fluorohexahydro-sila difenol ∼ himbacine ∼ AF-DX 384 ∼ AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M 3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M 1 and M 2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M 3 receptors.