Involvement of nitric oxide synthase and protein kinase C activation on chagasic antibodies action upon cardiac contractility.
We have already demonstrated the presence of antibodies in the sera of chagasic patients with the ability to interact with neurotransmitter receptors triggering several intracellular pathways of transduction signals. Here we show that, chagasic IgG induced protein kinase C (PKC) translocation to rat cardiac membranes and this effect was inhibited by muscarinic cholinergic blockers atropine and AF-DX 116 pointing to the participation of M2 receptors in this effect. It was also able to stimulate nitric oxide synthase (NOS) activity and this action was blunted by phospholipase C (PLC) and PKC inhibitors indicating that the production of nitric oxide (NO) would be the consequence of the cascade of enzymatic pathways triggered by mAChR activation. PKC and NOS activities were involved in chagasic IgG negative inotropic actions on rat isolated myocardium as its effects were blunted by staurosporine and L-N-monomethyl arginine. Furthermore, low concentrations of chagasic IgG inhibited the cardiac mechanical action of carbachol in a non-competitive manner. These data suggested that PKC activation in myocardium by chagasic IgG would be involved in its physiological actions by modulating NOS activity. The participation of PKC-mediated phosphorylation of mAChR leading to receptor desensitization as one of the causes of dysautonomia is also discussed.
Sterin-Borda
L
L
Cefybo-Conicet, Buenos Aires, Argentina.
Cremaschi
G
G
Genaro
A M
AM
Echagüe
A V
AV
Goin
J C
JC
Borda
E
E
D000818:Animals; D000913:Antibodies, Protozoan / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002598:Chagas Cardiomyopathy / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010276:Parasympatholytics / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000913:Antibodies, Protozoan; D007074:Immunoglobulin G; D010276:Parasympatholytics; D019323:omega-N-Methylarginine; D010890:Pirenzepine; D001285:Atropine; D002217:Carbachol; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; C048593:otenzepad