Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice

Sandeep Khurana, Ingrid Chacon, Guofeng Xie, Masahisa Yamada, Jurgen Wess, Jean Pierre Raufman, Richard H. Kennedy

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43 Scopus citations

Abstract

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 M 3R-/- 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.

Original languageEnglish (US)
Pages (from-to)127-132
Number of pages6
JournalEuropean Journal of Pharmacology
Volume493
Issue number1-3
DOIs
StatePublished - Jun 16 2004

Keywords

  • ATP
  • Cholinergic agonist
  • Receptor subtype
  • SIN-1
  • Vascular relaxation

ASJC Scopus subject areas

  • Pharmacology

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    Khurana, S., Chacon, I., Xie, G., Yamada, M., Wess, J., Raufman, J. P., & Kennedy, R. H. (2004). Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice. European Journal of Pharmacology, 493(1-3), 127-132. https://doi.org/10.1016/j.ejphar.2004.04.012