A SYNTHETIC PEPTIDE CORRESPONDING TO THE 2ND EXTRACELLULAR LOOP OF THE HUMAN M2 ACETYLCHOLINE-RECEPTOR INDUCES PHARMACOLOGICAL AND MORPHOLOGICAL-CHANGES IN CARDIOMYOCYTES BY ACTIVE IMMUNIZATION AFTER 6 MONTHS IN RABBITS

We have previously shown the presence of functional autoantibodies aga inst the second extracellular loop of the human M2 acetylcholine recep tor as an autoimmune epitope in 39% of patients with idiopathic dilate d cardiomyopathy (DCM), To see if this autoimmune DCM can be experimen tally reproduced, a synthetic peptide corresponding to the above autoi mmune epitope was used as an autoantigen to monthly immunize rabbits f or 6 months, Affinity-purified antibodies were able to display the neg ative chronotropic effects on neonatal rat cardiomyocytes in culture. The density of the M2 acetylcholine receptors was increased in the imm unized rabbits compared to controls but the receptors showed only low- affinity binding sites for the agonist carbachol, Ultrastructural chan ges such as moderate sarcolemma alterations, mitochondrial swelling, d isruption of cristae, and formation of myelin-like structures in the m yocardial cells of rabbits immunized for 6 months suggest an immune-in duced cardiotoxicity. With only a limited infiltration of inflammatory cells, these results point toward a pathophysiological role of anti-M 2 acetylcholine receptor autoantibodies. (C) 1996 Academic Press, Inc.