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. 2011 May;300(5):H1602-8.
doi: 10.1152/ajpheart.00982.2010. Epub 2011 Feb 18.

Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice

Adrian Gericke  1 , Jan J Sniatecki, Veronique G A Mayer, Evgeny Goloborodko, Andreas Patzak, Jürgen Wess, Norbert Pfeiffer
Affiliations

Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice

Adrian Gericke et al. Am J Physiol Heart Circ Physiol. 2011 May.

Abstract

Acetylcholine regulates perfusion of numerous organs via changes in local blood flow involving muscarinic receptor-induced release of vasorelaxing agents from the endothelium. The purpose of the present study was to determine the role of M₁, M₃, and M₅ muscarinic acetylcholine receptors in vasodilation of small arteries using gene-targeted mice deficient in either of the three receptor subtypes (M1R(-/-), M3R(-/-), or M5R(-/-) mice, respectively). Muscarinic receptor gene expression was determined in murine cutaneous, skeletal muscle, and renal interlobar arteries using real-time PCR. Moreover, respective arteries from M1R(-/-), M3R(-/-), M5R(-/-), and wild-type mice were isolated, cannulated with micropipettes, and pressurized. Luminal diameter was measured using video microscopy. mRNA for all five muscarinic receptor subtypes was detected in all three vascular preparations from wild-type mice. However, M(3) receptor mRNA was found to be most abundant. Acetylcholine produced dose-dependent dilation in all three vascular preparations from M1R(-/-), M5R(-/-), and wild-type mice. In contrast, cholinergic dilation was virtually abolished in arteries from M3R(-/-) mice. Deletion of either M₁, M₃, or M₅ receptor genes did not affect responses to nonmuscarinic vasodilators, such as substance P and nitroprusside. These findings provide the first direct evidence that M₃ receptors mediate cholinergic vasodilation in cutaneous, skeletal muscle, and renal interlobar arteries. In contrast, neither M₁ nor M₅ receptors appear to be involved in cholinergic responses of the three vascular preparations tested.

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Figures

Fig. 1.
Fig. 1.
Relative mRNA expression of individual muscarinic receptor subtypes (M1–M5) normalized to β-actin transcripts in cutaneous (A), skeletal muscle (B), and renal interlobar (C) arteries from wild-type mice. In each vascular bed, mRNA for all five muscarinic receptor subtypes was detected, but the highest expression levels were found for the M3 receptor. *P < 0.05, M3 receptor vs. all other subtypes. #P < 0.01, M3 receptor vs. all other subtypes (n = 5–7/artery group).
Fig. 2.
Fig. 2.
Responses of cutaneous (A), skeletal muscle (B), and renal interlobar (C) arteries from wild-type and M1, M3, and M5 receptor knockout mice (M1R−/−, M3R−/−, and M5R−/− mice, respectively) to acetylcholine. Vasodilation to acetylcholine was negligible in all three preparations from M3R−/− mice, whereas deletion of the M1 or M5 receptor gene had no significant effect on acetylcholine-induced responses. *P < 0.05, M3R−/− vs. all other groups (n = 8–12/concentration and genotype).
Fig. 3.
Fig. 3.
Responses of cutaneous (A), skeletal muscle (B), and renal interlobar (C) arteries to acetylcholine (10−4 mol/l) were virtually abolished after incubation with atropine (10−5 mol/l). *P < 0.05 (n = 6–8/genotype).
Fig. 4.
Fig. 4.
Responses of cutaneous (A), skeletal muscle (B), and renal interlobar arteries (C) from wild-type, M1R−/−, M3R−/−, and M5R−/− mice to carbachol (10−4 mol/l). Vasodilation to carbachol was negligible in all three preparations from M3R−/− mice, whereas deletion of the M1 or M5 receptor gene had no significant effect on carbachol-induced responses. #P < 0.01, M3R−/− vs. all other groups (n = 8–10/genotype).
Fig. 5.
Fig. 5.
Responses of cutaneous (A), skeletal muscle (B), and renal interlobar (C) arteries from wild-type, M1R−/−, M3R−/−, and M5R−/− mice to substance P. Deletion of either the M1, M3, or the M5 receptor did not affect responses to this endothelium-dependent vasodilator (n = 7–9/concentration and genotype).
Fig. 6.
Fig. 6.
Responses of cutaneous (A), skeletal muscle (B), and renal interlobar (C) arteries from wild-type, M1R−/−, M3R−/−, and M5R−/− mice to nitroprusside (10−5 mol/l). Deletion of either the M1, M3, or the M5 receptor did not affect responses to nitroprusside (n = 8–11/genotype).
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