Altered dynamic heart rate control in M₂-muscarinic acetylcholine receptor knockout mice

Abstract

It is thought that the initial increase in heart rate (HR) at the onset of dynamic exercise is caused by rapid withdrawal of cardiac parasympathetic tone, but not by an increase in sympathetic nerve activity. The M₂ receptor (of M₁-M₅ muscarinic receptors) is believed to be predominantly expressed in cardiac muscle. Therefore, we examined the role of M₂ receptor in HR control during voluntary wheel running exercise using M₂-KO mice. HR was determined by electrocardiogram telemetry in conscious mice. M₂-KO mice showed slight tachycardia and more diminished respiratory oscillations in HR than wild type (WT) mice at rest. Muscarinic agonist bethanechol induced marked vagal bradycardia and respiratory oscillations in HR in WT, but not in M₂-KO mice. With the onset of exercise, HR increased rapidly and remained elevated throughout exercise. This initial HR increase was blunted by a β-adrenergic blocker propranolol in both groups. A gradual increase in respiratory oscillation of HR observed in WT was absent in M₂-KO mice after exercise cessation. These results indicate that vagal bradycardia and the respiratory sinus arrhythmia in the inactive state are chiefly mediated by the M₂ receptor, whereas cardiac acceleration at the onset and during dynamic exercise is not solely mediated by it. In conclusion, the parasympathetic component plays a more important role in lowering HR from activated levels. [Jpn J Physiol 54 Suppl:S98 (2004)]