We have previously shown that a
peptide corresponding to the sequence of the second extracellular loop of the human muscarinic-2 (M2) receptor (M2-peptide) was able to induce an autoimmune
cardiomyopathy in rabbits. In this study, we investigated the effect of M2-antagonist (
otenzepad) on M2-peptide-induced
cardiomyopathy in rabbits. New Zealand White rabbits were divided into four groups: 1) control group, saline injection; 2) M2-
peptide group, M2-
peptide injection; 3) M2-antagonist group,
otenzepad (30 mg/day) orally and saline injection; and (4) M2-antagonist + M2-
peptide group,
otenzepad (30 mg/day) orally and M2-
peptide injection. The study duration was 1 year. Saline or
peptide was injected once a month. All rabbits in both the M2-
peptide group and the M2-antagonist + M2-
peptide group had high titers of anti-M2-
autoantibodies in their sera. Rabbits in the M2-
peptide group showed an increase in heart weight, wall thinning and dilatation of the right ventricle. On the contrary, rabbits in the M2-antagonist + M2-
peptide group had normal heart weight and shape. All rabbits in the M2-
peptide group showed multifocal degeneration and
necrosis of myocardial cells with moderate infiltration of inflammatory cells, while four rabbits in the M2-antagonist + M2-
peptide group showed slight infiltration of inflammatory cells with normal myocardial cells and interstitium, and another three showed no histological changes in the hearts. In conclusion, M2-antagonist protects the myocardium from injury induced by autoimmune mechanism against
M2-muscarinic receptor.