Cardiac Muscarinic Receptors Decrease with Age

The M 1 muscarinic receptor antagonist pirenzepine in low doses decreases resting heart rate; this effect declines with age (Poller, U., G. Nedelka, J. Radke, K. Pönicke, and O.-E. Brodde. 1997. J. Am. Coll. Cardiol. 29:187–193). To study possible mechanisms underlying this effect, 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.] bolus) 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 nodes; and ( c ) in right atria from 39 patients of different ages (5 d–76 yr) undergoing open heart surgery, M 2 muscarinic receptor density (by [ 3 H] Nmethylscopolamine binding) and adenylyl cyclase activity. ( a ) Pirenzepine at both doses decreased heart rate in young volunteers significantly more than in older volunteers; ( b ) pirenzepine ( , 1 mg) decreased resting heart rate in the recipient’s native but not transplanted sinus node; and ( c ) M 2 receptor density and carbachol-induced inhibition of forskolin-stimulated adenylyl cyclase activity decreased significantly with the age of the patients. We conclude that pirenzepine 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 atrial M 2 receptor density and function decrease. ( J. Clin. Invest. 1998. 101:471-478.)