CARDIAC MUSCARINIC RECEPTORS DECREASE WITH AGE - IN-VITRO AND IN-VIVOSTUDIES

The M-1 muscarinic receptor antagonist pirenzepine in low doses decrea ses resting heart rate; this effect declines with age (Poller, U., G. Nedelka, J. Radke, K. Ponicke, and O.-E. Brodde. 1997. J. Am. Cell. Ca rdiol. 29:187-193). To study possible mechanisms underlying this effec t, we assessed (a) in six young (26 yr old) and six older volunteers ( 61 yr old), pirenzepine effects (0.32 and 0.64 mg intravenous [i.v.] b olus) on isoprenaline-induced heart rate increases; (b) in five heart transplant recipients, pirenzepine effects (0.05-10 mg i.v. bolus) on resting heart rate in the recipient's native and transplanted sinus no des; and (c) in right atria from 39 patients of different ages (5 d-76 yr) undergoing open heart surgery, M-2 muscarinic receptor density (b y [H-3]N-methyl-scopolamine binding) and adenylyl cyclase activity. (a ) Pirenzepine at both doses decreased heart rate in young volunteers s ignificantly more than in older volunteers; (b) pirenzepine (< 1 mg) d ecreased resting heart rate in the recipient's native but not transpla nted sinus node; and (c) M-1 receptor density and carbachol-induced in hibition of forskolin-stimulated adenylyl cyclase activity decreased s ignificantly with the age of the patients. We conclude that pirenzepin e decreases heart rate via inhibition of presynaptic M-1 autoreceptors , thereby releasing endogenous acetylcholine, and that the heart rate- decreasing effect of acetylcholine declines with age because right atr ial Mt receptor density and function decrease.