Age-related changes in electrophysiological responses to muscarinic receptor stimulation in rat myocardium

Abstract

Recent studies have demonstrated that the negative chronotropic and inotropic responses of the heart to cholinergic muscarinic receptor stimulation are strikingly enhanced with aging in the rat model. The present study investigated the electrophysiological basis of this phenomenon by determining the effects of a muscarinic receptor agonist, carbachol, on transmembrane action potential parameters in right atrial tissue and right ventricular free wall preparations from adult (6-8 months old) and aged (26-28 months old) Fischer 344 rats. In addition, the effect of carbachol on atrioventricular conduction time (AVT) was determined in isolated perfused beating hearts. The results showed the following. The baseline maximum diastolic potential (MDP: adult, -76.4 +/- 1.8 mV; aged, -66.8 +/- 1.5 mV; p < 0.05; n = 5) but not the action potential duration measured at 95% repolarization (APD95: adult, 40.0 +/- 5.0 ms; aged, 47.4 +/- 6.7 ms; n = 5) differed significantly in aged compared with adult atrium. No significant age-related difference was evident in baseline MDP measured in ventricular epicardium (adult, -69.8 +/- 0.5 mV; aged, -69.0 +/- 1.1 mV; n = 6) or endocardium (adult, -72.5 +/- 1.4 mV; aged, -73.0 +/- 1.2 mV; n =6). The baseline action potential duration measured at 50% repolarization (APD50) differed significantly with age in ventricular endocardium (adult, 11.6 +/- 2.2 ms; aged, 23.0 +/- 4.6 ms; p < 0.05; n =6) but not in epicardium (APD50: adult, 8.1 +/- 0.4 ms; aged, 13.0 +/- 2.3 ms; n = 6). Superfusion with carbachol (0.1 nM - 10 mu M) resulted in concentration-dependent hyperpolarization of MDP in atrium; the magnitude of hyperpolarization differed significantly with age (2.5-fold higher in the aged; p < 0.05; n = 5). Carbachol caused concentration-dependent shortening of APD50; this effect differed significantly with age in the ventricle (2-fold greater in the aged; p < 0.05; n = 6) but not in the atrium. Carbachol prolonged the AVT in atrial-paced (240 beats/min) hearts; the magnitude of carbachol-induced increase in AVT did not differ significantly with age. These results are consistent with the possibility that in the aging heart, greater hyperpolarization at the level of the right atrium (likely involving pacemaker cells) and greater shortening of APD50 at the level of ventricular myocytes may contribute to the enhanced cholinergic-triggered bradycardia and negative inotropic response, respectively.