Pharmacological characterization of muscarinic receptors mediating acetylcholine-induced contraction and relaxation in rabbit intrapulmonary arteries.
Rabbit pulmonary arteries exhibit a biphasic response to acetylcholine consisting of an endothelium-dependent contraction in tissues at resting tone and an endothelium-dependent relaxation in vessels with elevated tone. Each response was studied separately by treating the arteries with inhibitors of nitric oxide synthase to block the relaxant response or with inhibitors of cyclooxygenase to inhibit the contractile response. In the present study, experiments in isolated pulmonary arteries were undertaken to characterize the muscarinic receptor subtypes mediating the two separate responses by utilizing subtype-selective antagonists and determining pA2 values of the antagonists through Schild analysis. Both the relaxant and the contractile responses were inhibited most potently by atropine and by the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide. The pA2 values for inhibition of the contractile and relaxant responses were 9.44 and 8.79 for atropine and 8.92 and 9.29 for 4-diphenylacetoxy-N-methylpiperidine methiodide, respectively. The M1-selective antagonist pirenzepine and the M2-selective antagonist (11-([2-[(diethylamino)methyl]-1-piperidinyl]- acetyl)-5, 11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one) displayed much lower affinities for the muscarinic receptors mediating these responses. The pA2 values for inhibition of the contractile and relaxant responses were 6.77 and 6.74 for pirenzepine and 6.06 and 5.70 for (11-([2-[(diethylamino)methyl]-1-piperidinyl] acetyl)-5, 11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one), respectively.
School of Pharmacy, University of Colorado Health Sciences Center, Denver.
R J
RJ
Altiere
D C
DC
Travis
J
J
Roberts
D C
DC
Thompson
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects / Q000648:ultrastructure; D007082:Ileum / Q000187:drug effects / Q000648:ultrastructure; D008168:Lung / Q000098:blood supply*; D008297:Male; D018727:Muscarinic Antagonists / Q000145:classification*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D011817:Rabbits; D011976:Receptors, Muscarinic
D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D000109:Acetylcholine; C048593:otenzepad