DIFFERENTIAL CHOLINOCEPTOR SUBTYPE-DEPENDENT ACTIVATION OF SIGNAL-TRANSDUCTION PATHWAYS IN NEONATAL VERSUS ADULT-RAT ATRIA

In this study, we investigated the expression and distribution of musc arinic cholinergic receptors (mAChRs) and the different signaling path ways associated with mAChR activation in atria isolated from adult and neonatal rats. Carbachol stimulation of mAChRs in both neonatal and a dult rat atria led to a negative inotropic response with activation of phosphoinositide hydrolysis, an increase in cyclic GMP levels, and a decrease in cyclic AMP production. However, compared with adult atria, neonatal atria showed hypersensitivity in the contractile effect indu ced by carbachol. Pharmacological analysis with mAChR antagonists indi cated that M-1 and M-2 mAChR subtypes are important mediators of the r esponse to carbachol in neonatal atria. In contrast, in adult atria th e effect of the agonist was coupled only to the M-2 mAChR subtype. Mor eover, an increased number of total mAChRs was labeled in neonatal atr ial membranes compared with those of adults. Although a predominant M- 2 mAChR population is expressed in atria at both stages of development studied, competition binding parameters calculated for carbachol indi cated the presence of high-affinity binding sites, with higher affinit y in neonates than in adults. These results suggest that the differenc es observed between neonatal and adult atria in their response to a ch olinergic agonist may be related to differential expression of mAChR s ubtypes and/or changes in functional coupling of mAChR subtypes during development. (C) 1997 Elsevier Science Inc.