Beneficial effect of muscarinic-2 antagonist on dilated cardiomyopathy induced by autoimmune mechanism against muscarinic-2 receptor.

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.