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Autonomic interactions in the aging heart: age-associated decrease in muscarinic cholinergic receptor mediated inhibition of beta-adrenergic activation of adenylate cyclase



Autonomic interactions in the aging heart: age-associated decrease in muscarinic cholinergic receptor mediated inhibition of beta-adrenergic activation of adenylate cyclase



Mechanisms of Ageing and Development 34(3): 249-259



The ability of the muscarinic receptor agonist, carbachol, to inhibit beta-adrenergic activation of adenylate cyclase was examined in cardiac membranes from 6-month (young adult) and 24-month (aged) old rats in an effort to assess the effect of aging on adrenergic-cholinergic interactions in the heart. At varying concentrations (0.1-100 microM) of carbachol, GTP plus isoproterenol-stimulated adenylate cyclase activity was inhibited 5-39% in cardiac membranes from 6-month-old rats; this inhibition was statistically significant at all but the lowest concentration (0.1 microM) of carbachol used. In contrast, in cardiac membranes from 24-month-old rats, the inhibition of GTP plus isoproterenol-stimulated adenylate cyclase activity by carbachol was very weak (3-20% with 0.1-100 microM carbachol), and statistically insignificant. The muscarinic receptor antagonist, atropine, blocked the inhibition of GTP plus isoproterenol-stimulated enzyme activity by carbachol showing that the observed inhibitory effect of carbachol was muscarinic receptor dependent. The basal adenylate cyclase activity (which showed no significant age-related difference) was unaffected by carbachol. No significant age-related differences were evident in: (a) the concentration of carbachol required for half-maximal inhibition of GTP plus isoproterenol-stimulated adenylate cyclase activity; (b) the density of muscarinic receptor sites; and (c) their agonist and antagonist binding affinities. The GTP plus isoproterenol-stimulated cyclase activity measured in the absence of carbachol was approximately 70% lower in cardiac membranes from 24-month-old, compared to 6-month-old rats, confirming an age-associated decline in beta-adrenergic activation of the cyclase observed in our previous study [Mech. Ageing Dev., 19: (1982) 127-139]. The above findings suggest an apparent age-related decline in the postsynaptic antiadrenergic action of cholinergic stimulus in the heart; thus, exaggerated cholinergic antagonism of beta-adrenergic stimulus does not seem to contribute to the impaired adrenergic control of the heart in aging. On the other hand, autonomic imbalance, due to excessive weakening of the antiadrenergic influence of cholinergic stimulus, may compromise the ability of the cholinergic system to counteract the tendency of unrestrained adrenergic drive to increase ventricular vulnerability to fibrillation; this, in turn, may favor the high incidence of cardiac arrhythmias in aging.

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Accession: 039355287

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PMID: 3014235


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