15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and 4-diphenylacetoxy-1-1-dimethylpiperidinium

Information about the muscarinic receptor subtype(s) mediating pulmonary circulatory vasodilator responses to acetylcholine (ACh) is limited. The aim of this study was to pharmacologically characterize the muscarinic receptors associated with ACh-induced pulmonary vasodilation in a pulmonary hypertension model. Vasodilation of rabbit isolated buffer-perfused lungs in which pulmonary hypertension was induced with the thromboxane A₂ analogue U-46619 was evoked by ACh at a just maximally effective concentration (2 x 10⁻⁷ M). The effects of cumulative concentrations of three specific muscarinic receptor subtype antagonists [pirenzepine (M₁), methoctramine (M₂), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M₃] on ACh-induced pulmonary vasodilation were determined. Double vascular occlusion pressure was recorded to locate the muscarinic receptors within the pulmonary vasculature. Based on the 50% inhibitory concentrations (IC₅₀), the rank of order of antagonist potency was 4-DAMP >> pirenzepine > methoctramine. The vascular effects of all three inhibitors were localized to the precapillary segment. These findings suggest that the vasodilator action of ACh on rabbit isolated perfused U-46619 pretreated lungs is mediated by M₃ muscarinic receptors located in the pulmonary arterial bed.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Diamines; Hypertension, Pulmonary; Lung; Piperidines; Pirenzepine; Rabbits; Receptor, Muscarinic M3; Vasodilation

Muscarinic receptors of resistance vessels (submucosal arterioles, outside diameter 50-75 microns) from the guinea-pig small intestine were investigated in vitro using a computer-assisted videomicroscopy system (Diamtrak). The muscarinic receptor which mediates vasodilation of precontracted [U-46619 (300 nM) or (-)-noradrenaline (10 microM)] arterioles was characterized with several muscarinic agonists and subtype-selective antagonists. The following agonists all produced equivalent maximum vasodilation (given in rank order of potency): acetylcholine = arecaidine propargyl ester (APE) greater than oxotremorine = (+/-)-muscarine = (+/-)-methacholine greater than carbachol greater than 4-[[N-(4-chlorophenyl)carbamoyl]oxy]-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). 4-[[N-(3-Chlorophenyl)-carbamoyl]oxy]-2-butynyltrimethylammonium chloride (McN-A-343) and N-ethyl-guvacine propargyl ester (NEN-APE) produced minimal or no arteriolar vasodilation. The muscarinic antagonists pirenzepine, (+-)-5,11-dihydro-11-[[[2-[2-((dipropylamino)methyl)-1-piperidinyl] ethyl]amino]-carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one (AF-DX 384), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one (AQ-RA 741), p-fluorohexahydro-sila-difenidol (p-F-HHSiD), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and (R)- and (S)-hexahydro-difenidol [(R)-HHD, (S)-HHD] shifted the muscarine, methacholine or carbachol dose-response curve to the right in a competitive manner. Schild analysis of the data yielded pA2 values for pirenzepine (6.74/6.9), AF-DX 384 (6.72), AQ-RA 741 (6.58), p-F-HHSiD (7.53/7.57), 4-DAMP (9.06), (R)-HHD (7.88/8.32) and (S)-HHD (5.52/5.88). Thus, it can be concluded that submucosal arterioles possess only the M3 functional muscarinic receptor, the activation of which causes blood vessel dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Arterioles; Benzodiazepinones; Carbachol; Guinea Pigs; Ileum; Methacholine Chloride; Muscarine; Muscarinic Antagonists; Oxotremorine; Parasympatholytics; Parasympathomimetics; Piperidines; Pirenzepine; Prostaglandin Endoperoxides, Synthetic; Receptors, Muscarinic; Vasodilation