M3 and M1 receptors in cerebral arterioles in vivo: evidence for downregulated or ineffective M1 when endothelium is intact.
Pial arterioles of mice were monitored by intravital television microscopy. Responses to acetylcholine (ACh) and to McN-A-343, a selective M1 activator, were monitored before and after endothelial injury by a laser-dye technique in the presence or absence of different reference antagonists to the M1, M2, and M3 muscarinic receptors. ACh and McN-A-343 produced endothelium-dependent dilation that was blocked by 4-diphenyl-N-methyl-piperidine methiodide, an inhibitor of the M3 receptor. Dilations were not augmented by blocking the M1 receptor with pirenzepine. Endothelial injury unmasked a constricting effect of both ACh and McN-A-343. The constricting effect was blocked by pirenzepine. The results support the literature suggesting an action of McN-A-343 at more than one site. They indicate that ACh causes endothelium-dependent relaxation via the M3 receptor and directly constricts vascular smooth muscle via the M1 receptor. There does not appear to be continuous competition between endothelium-dependent relaxation and endothelium-independent constriction. Rather the M1 receptors mediating constriction in vascular smooth muscle appear downregulated and/or uncoupled from the contractile machinery as long as the overlying endothelium synthesizes/releases the mediator (endothelium-derived relaxing factor) of ACh's dilating action.
Shimizu
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Department of Pathology (Neuropathology), Virginia Commonwealth University-Medical College of Virginia, Richmond 23298-0017.
Rosenblum
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WI
Nelson
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D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000378:metabolism*; D001921:Brain / Q000098:blood supply*; D003959:Diamines / Q000494:pharmacology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000502:physiology*; D007834:Lasers; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists; D010841:Pia Mater / Q000098:blood supply; D010890:Pirenzepine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014544:Uridine Triphosphate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D003959:Diamines; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D000109:Acetylcholine; C054938:methoctramine; D014544:Uridine Triphosphate