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J Biol Chem, Vol. 273, Issue 48, 32158-32166, November 27, 1998

Signaling Mechanisms Underlying Muscarinic Receptor-mediated Increase in Contraction Rate in Cultured Heart Cells

From the Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642

We have investigated the mechanisms by which stimulation of cardiac muscarinic receptors result in paradoxical stimulatory effects on cardiac function, using cultured neonatal rat ventricular myocytes as a model system. Application of low concentrations of carbachol (CCh) (EC₅₀ = 35 nM) produced an atropine-sensitive decrease in spontaneous contraction rate, while, in cells pretreated with pertussis toxin, higher concentrations of CCh (EC₅₀ = 26 µM) elicited an atropine-sensitive increase in contraction rate. Oxotremorine, an m₂ muscarinic acetylcholine receptor (mAChR) agonist, mimicked the negative but not the positive chronotropic response to CCh. Reverse transcription followed by polymerase chain reaction carried out on mRNA obtained from single cells indicated that ventricular myocytes express mRNA for the m₁, m₂, and, possibly, m₄ mAChRs. The presence of m₁ and m₂ mAChR protein on the surface membranes of the cultured ventricular myocytes was confirmed by immunofluorescence. The CCh-induced positive chronotropic response was significantly inhibited by fluorescein-tagged antisense oligonucleotides directed against the m₁, but not the m₂ and m₄, mAChR subtypes. The response was also inhibited by antisense oligonucleotides against G_q protein. Finally, inhibition of CCh-induced phosphoinositide hydrolysis with 500 µM neomycin or 5 µM U73122 completely abolished the CCh-induced positive chronotropic response. These results are consistent with the stimulatory effects of mAChR activation on the rate of contractions in cultured ventricular myocytes being mediated through the m₁ mAChR coupled through G_q to phospholipase C-induced phosphoinositide hydrolysis.

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