Muscarinic modulation of cardiac rate at low acetylcholine concentrations

Slowing of cardiac pacemaking induced by cholinergic input is thought to arise from the opening of potassium channels caused by muscarinic receptor stimulation. In mammalian sinoatrial node cells, however, muscarinic stimulation also inhibits the hyperpolarization-activated current (If), which is involved in the generation of pacemaker activity and its acceleration by catecholamines. Acetylcholine at nanomolar concentrations inhibits If and slows spontaneous rate, whereas 20 times higher concentrations are required to activate the acetylcholine-dependent potassium current (IK,ACh). Thus, modulation of If, rather than IK,ACh, is the mechanism underlying the muscarinic control of cardiac pacing at low (nanomolar) acetylcholine concentrations.