Muscarinic receptor subtype mediating vasodilation in feline middle cerebral artery exhibits M3 pharmacology

doi:10.1016/0014-2999(90)90476-M

European Journal of Pharmacology

Volume 178, Issue 2, 20 March 1990, Pages 203-213

https://doi.org/10.1016/0014-2999(90)90476-M Get rights and content

Abstract

The nature of the muscarinic receptor subtype mediating the endothelium-dependent relaxation of the cat middle cerebral artery was investigated in vitro by recording the smooth muscle isometric tension of precontracted arterial segments. Relaxation induced by several agonists (acetylcholine (ACh), acetyl-β-methylcholine, oxotremorine, carbachol and McN-A-343) was recorded. The ability of selective (pirenzepine, dicyclomine, adiphenine, AF-DX 116, methoctramine, gallamine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and hexahydro-sila-difenidol (HHSiD)) and non-selective antagonists (atropine, scopolamine and quinuclidinyl benzilate (QNB)) to block the relaxation induced by ACh was also estimated. The weak activity of the poorly selective M₁ agonist McN-A-343 together with the intermediate affinity of pirenzepine and adiphenine tend to exclude the M₁ muscarinic receptor as the primary mediator of the cholinergic relaxation. The low affinity of AF-DX 116 and methoctramine further suggested that the cerebrovascular muscarinic receptor does not correspond to the M₂ cardiac sybtype. In contrast, 4-DAMP and HHSiD potently inhibited the ACh-induced relaxation with affinities similar to those reported at the M₃ glandular receptor. We conclude that a site similar to the pharmacological M₃ muscarinic receptor subtype is responsible for the cholinergic relaxation of the cat middle cerebral artery.

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Citation Excerpt :
Intracerebroventricular injection of McN-A-343 can activate a central cholinergic anti-inflammatory pathway in the vagus nerve that inhibits peripheral production of tumor necrosis factor (TNF) and thus protects from endotoxemia and sepsis (Pavlov et al., 2006). McN-A-343 activated muscarinic receptors in the prepositus hypoglossi nucleus involved in the cholinergic pathway contributing to persistent neural activation necessary for eye-fixation (Delgado-Garcia et al., 2006). Central administration of McN-A-343 into the rat lateral hypothalamic nucleus stimulated pancreatic enzyme secretion (Li et al., 2003) (see Section 4.3: Pancreas).
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This chapter discusses the various receptor mediated events in the microcirculation focusing on the various kinds of receptors. Epinephrine (Epi) and norepinephrine (NE) are the main endogenous catecholamines mediating sympathetic regulation of the microcirculation. Both vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) express multiple adrenoceptor subtypes. All three α₁-adrenoceptor subtypes contribute to vasoconstriction in the microcirculation. The diverse family of adrenoceptors mediates multiple important but opposing effects in the microcirculation. Dopamine receptors are grouped into the D₁ and D₂ families. Dopamine is thought to bind to five subtypes of receptors. Microcirculatory effects of the D₁ and D₂ receptor families have been reported, with primary focus on the D₁ family. -hydroxytryptamine (5-HT, serotonin) has a rich history in the vasculature. The detection of M₁, M₃, and possibly M₅ muscarinic receptor subtypes in brain microcirculation is consistent with reports showing that these receptors mediate vasoconstriction, vasodilatation, and activation of nitric oxide synthase. ANG II receptors have a variety of important influences in the control of the vasculature and especially the microcirculation. ANG II has multiple actions in the vasculature, including regulation of vascular tone, microvessel density (MVD) and vascular structure. Arginine vasopressin receptors, endothelin receptors, adrenomedullin/cgrp receptors, adenosine receptors, purinergic receptors, kinin receptors, histamine receptors, eicosanoid receptors, and growth factor receptors are also explored.
Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M<inf>3</inf>R<sup>-/-</sup> mice
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Acetylcholine interacts with endothelial muscarinic receptors to enhance nitric oxide (NO) release and thereby cause vasodilation. The present study was designed to determine if this effect of acetylcholine is mediated by muscarinic M₃ receptors. Thoracic aortae were isolated from wild-type (WT) and M₃ receptor knock out (M₃R^−/−) male mice, and endothelium-intact (I) and -denuded (D) aortic rings were bathed in physiological buffer. Preparations were utilized to examine the contractile response to phenylephrine (1×10⁻⁸–3×10⁻⁴ M added cumulatively) and the vasodilatory actions of acetylcholine (10⁻⁸–10⁻⁴ M), carbachol (10⁻⁹–10⁻⁴ M), ATP (3×10⁻⁵ M) and the NO donor SIN-1 (10⁻⁴ M), each added in the presence of phenylephrine. Endothelium-dependent vasodilatory effects of acetylcholine and carbachol were obvious in aortae isolated from WT mice (56.3±9.8% and 49.1±4.1% reductions, respectively, in phenylephrine-induced contraction; p<0.05), while acetylcholine and carbachol-associated relaxations observed in endothelium-intact M₃R^−/− preparations (17.9±2.6% and 13.5±4.2% reductions, respectively) did not differ significantly from time-control values. ATP-induced, endothelium-dependent vasodilation was similar in preparations from M₃R^−/− and WT mice, and SIN-1 elicited similar dilatory effects in intact and denuded WT and M₃R^−/− segments. Phenylephrine concentration–response curves were shifted leftwards by removal of the endothelium in both groups (EC₅₀ values: WT-I/D—25.59±6.86/3.13±1.01×10⁻⁷ M; M₃R^−/−I/D—13.92±4.21/1.52±0.46×10⁻⁷ M; both p<0.05); however, the phenylephrine response did not differ significantly when compared between the WT and M₃R^−/− groups. These results indicate that the attenuated vasodilatory effect of acetylcholine in endothelium-intact aortae from M₃R^−/− mice is due to the absence of muscarinic M₃ receptors, and thus suggest that in mouse aorta, muscarinic M₃ receptors play a major role in the endothelium-dependent acetylcholine-induced vasodilation.
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Muscarinic receptor subtype mediating vasodilation in feline middle cerebral artery exhibits M3 pharmacology

Abstract

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Br. J. Pharmacol.

The affinity of some selective muscarinic receptor antagonists for the muscarinic receptor mediating endothelial-dependent relaxation of the rabbit and rat thoracic aorta

J. Pharm. Pharmacol.

General Pharmacology

Pharmacological profile of the muscarinic receptor mediating relaxation in feline middle cerebral artery

Affinity of muscarinic receptor antagonists for three putatuve muscarinic receptor binding sites

Br. J. Pharmacol.

Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2 and M3 receptors

J. Pharmacol. Exp. Ther.

Muscarinic receptor subtype mediating vasodilation in feline middle cerebral artery exhibits M₃ pharmacology

Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M₁, M₂ and M₃ receptors