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 th e second extracellular loop of the human muscarinic-2 (M2) receptor (M2-pep tide) was able to induce an autoimmune cardiomyopathy in rabbits. In this s tudy, 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-pep tide 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 ventri cle. On the contrary, rabbits in the M2-antagonist + M2-peptide group had n ormal heart weight and shape. All rabbits in the M2-peptide group showed mu ltifocal degeneration and necrosis of myocardial cells with moderate infilt ration 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 myocardiu m from injury induced by autoimmune mechanism against M2-muscarinic recepto r.