INTERACTION OF CYTOTOXIC T-LYMPHOCYTES AND GUINEA-PIG VENTRICULAR MYOCYTES - PHARMACOLOGICAL MODULATION BY BLOCKING K-LYMPHOCYTES( CURRENTSIN CYTOTOXIC T)

Infiltrating cytotoxic T lymphocytes (CTLs) are important immune effec ters that damage the myocardium during heart transplant rejection as w ell as in cardiomyopathy and Chagas' heart disease. We have previously shown that in an in vitro model of murine-derived peritoneal exudate CTL (PEL)-guinea pig ventricular myocyte interaction, PEL induced in c onjugated myocytes reduction of resting membrane potential and action potential (AP) amplitude, shortening of AP duration, delayed afterdepo larizations (DADs), and myocyte contracture and destruction. Since the se findings indicated that cytotoxicity was largely caused by [Ca2+](i ) overload, in the present study we tested the hypothesis that blockin g the L-type Ca2+ current (I-Ca,I-L) in the myocyte will eliminate the trigger for Ca2+ release from intracellular stores and will reduce [C a2+](i) overload and subsequent myocyte deterioration. CoCl2 (3 mmol/L ) prevented PEL-induced AP changes, induction of DADs, and myocyte des truction. Since verapamil (2 mu mol/L) was ineffective, indicating tha t the CoCl2 protection was not due to block of I-Ca,I-L we tested whet her the different action of these Ca2+ channel blockers was due to the ir differential effect on the PEL's K+ current (I-K), previously shown to participate in lymphocyte activation and cytotoxicity. In agreemen t with their protective efficacy, CoCl2, but not verapamil blocked I-K in PELs, suggesting that this is the mechanism for the protection pro vided by CoCl2. To support this notion, we tested the effect of the sc orpion-derived peptide margatoxin (10 nmol/L), a specific K+ channel b locker in lymphocytes, on PEL-myocyte interaction and on PEL's I-K; ma rgatoxin prevented PEL-induced cytotoxicity and also blocked I-K in PE L. Based on these findings, an alternative modality for attenuating CT L-induced lymphocytotoxicity is proposed.