cyclic-gmp and cyanopindolol

It has been proposed that anti-myocardial antibodies (Ab) against neurotransmitter (NT) receptors are involved in the immunopathology of chronic Chagas' heart disease. We demonstrated that an anti-Trypanosoma cruzi monoclonal Ab (mAb), CAK20.12, binds to murine cardiac beta-adrenergic and muscarinic acetyl choline (mACh) receptors eliciting abnormal physiological responses on normal heart. No cross-linking requirement for mAb actions was demonstrated using Fab fragment derived from CAK20.12. mAb binding to synthetic peptides from the second extracellular loop of both beta1-adrenergic and mACh receptors, demonstrated by ELISA, identified the region of NT receptors involved. Cross-reactivity between these peptides and T. cruzi antigen was confirmed by binding inhibition assays. These results support the existence of cross-reactivity due to molecular mimicry between a parasite antigen and the major antigenic epitopes present on both beta1-adrenergic and M2-ACh receptors. Its possible relationship with cardiac dysfunction during chronic stage of Chagas' disease is also discussed.

Topics: Adrenergic beta-Antagonists; Analysis of Variance; Animals; Antibodies, Monoclonal; Antibodies, Protozoan; Binding, Competitive; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Epitopes; Immunoglobulin Fab Fragments; In Vitro Techniques; Iodine Isotopes; Mice; Mice, Inbred BALB C; Muscarinic Antagonists; Myocardial Contraction; Pindolol; Quinuclidinyl Benzilate; Radioimmunoassay; Radioligand Assay; Receptor, Muscarinic M2; Receptors, Adrenergic, beta-1; Titrimetry; Trypanosoma cruzi

We studied beta-adrenergic and muscarinic cholinergic receptor (MR) expression and proliferative response in lymphocytes from animals under chronic mild stress (CMS) model of depression (CMS animals). Animals were subjected to CMS (periods of food or water deprivation, changes in lighting conditions, tilted cage, etc.) for 12 weeks. CMS lymphocytes showed an altered mitogen-induced proliferation. CMS-B and -T lymphocytes showed an increment on beta-adrenoceptor number and on intracellular responses to a beta-agonist. CMS-T cells showed higher MR expression and lower cGMP responses than normal lymphocytes. MR were not detectable in normal B cells while CMS-B cells showed both MR expression and cGMP response. Beta and muscarinic stimulation influenced lymphocyte proliferative responses, in accordance with cAMP and cGMP responses. After 12 weeks of the CMS procedure, animals were treated with fluoxetine while the CMS procedure continued. Fluoxetine treatment reverted the alterations induced by CMS. These findings suggest a possible mechanism for the immune alterations found in depressive disorders and for the effect of fluoxetine treatment on immune response.

Topics: Adrenergic beta-Antagonists; Animals; Antidepressive Agents, Second-Generation; Autonomic Nervous System; B-Lymphocytes; CD4-CD8 Ratio; Cell Division; Chronic Disease; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Female; Fluoxetine; Iodine Radioisotopes; Mice; Mice, Inbred BALB C; Mitogens; Muscarinic Antagonists; Pindolol; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Adrenergic, beta; Receptors, Muscarinic; Stress, Psychological; T-Lymphocytes; Tritium