AGE-RELATED-CHANGES IN ELECTROPHYSIOLOGICAL RESPONSES TO MUSCARINIC RECEPTOR STIMULATION IN RAT MYOCARDIUM

Recent studies have demonstrated that the negative chronotropic and in otropic responses of the heart to cholinergic muscarinic receptor stim ulation are strikingly enhanced with aging in the rat model. The prese nt study investigated the electrophysiological basis of this phenomeno n by determining the effects of a muscarinic receptor agonist, carbach ol, on transmembrane action potential parameters in right atrial tissu e and right ventricular free wall preparations from adult (6-8 months old) and aged (26-28 months old) Fischer 344 rats. In addition, the ef fect of carbachol on atrioventricular conduction time (AVT) was determ ined in isolated perfused beating hearts. The results showed the follo wing. 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 po tential duration measured at 95% repolarization (APD(95): adult, 40.0 +/- 5.0 ms; aged, 47.4 +/- 6.7 ms; n = 5) differed significantly in ag ed compared with adult atrium. No significant age-related difference w as 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 actio n potential duration measured at 50% repolarization (APD(50)) 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 (A PD(50): adult, 8.1 +/- 0.4 ms; aged, 13.0 +/- 2.3 ms; n = 6). Superfus ion with carbachol (0.1 nM - 10 mu M) resulted in concentration-depend ent hyperpolarization of MDP in atrium; the magnitude of hyperpolariza tion differed significantly with age (2.5-fold higher in the aged; p < 0.05; n = 5). Carbachol caused concentration-dependent shortening of APD(50); 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. C arbachol prolonged the AVT in atrial-paced (240 beats/min) hearts; the magnitude of carbachol-induced increase in AVT did not differ signifi cantly with age. These results are consistent with the possibility tha t in the aging heart, greater hyperpolarization at the level of the ri ght atrium (likely involving pacemaker cells) and greater shortening o f APD(50) at the level of ventricular myocytes may contribute to the e nhanced cholinergic-triggered bradycardia and negative inotropic respo nse, respectively.