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.
Matsui
S
S
Department of Cardiology, Kanazawa Medical University, Uchinada, Ishikawa, Japan. matsui@kanazawa-med.ac.jp
Fu
M L
ML
Hayase
M
M
Katsuda
S
S
Yamaguchi
N
N
Teraoka
K
K
Kurihara
T
T
Takekoshi
N
N
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D007279:Injections, Subcutaneous; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D009206:Myocardium / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D011817:Rabbits; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000276:immunology*
D000889:Anti-Arrhythmia Agents; D018727:Muscarinic Antagonists; D010455:Peptides; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D010890:Pirenzepine; C048593:otenzepad