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(Circulation Research. 1996;78:253-261.)
© 1996 American Heart Association, Inc.

Articles

Interaction of Cytotoxic T Lymphocytes and Guinea Pig Ventricular Myocytes

Pharmacological Modulation by Blocking K⁺ Currents in Cytotoxic T Lymphocytes

Bella Felzen, Revital Lavy, Maria Garcia, Gideon Berke, Phyllis Gardner, Ofer Binah

From the Rappaport Family Institute for Research in the Medical Sciences (B.F., R.L., O.B.), Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; Merck Research Laboratories (M.G.), Rahway, NJ; the Department of Cell Biology (G.B.), Weizmann Institute of Science, Rehovot, Israel; and the Department of Molecular Pharmacology (P.G.), Stanford (Calif) University School of Medicine.

Correspondence to Ofer Binah, DSc, Rappaport Institute, PO Box 9697, Haifa 31096, Israel.

Abstract Infiltrating cytotoxic T lymphocytes (CTLs) are important immune effectors that damage the myocardium during heart transplant rejection as well 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 conjugated myocytes reduction of resting membrane potential and action potential (AP) amplitude, shortening of AP duration, delayed afterdepolarizations (DADs), and myocyte contracture and destruction. Since these findings indicated that cytotoxicity was largely caused by [Ca²⁺]_i overload, in the present study we tested the hypothesis that blocking the L-type Ca²⁺ current (I_Ca,L) in the myocyte will eliminate the trigger for Ca²⁺ release from intracellular stores and will reduce [Ca²⁺]_i overload and subsequent myocyte deterioration. CoCl₂ (3 mmol/L) prevented PEL-induced AP changes, induction of DADs, and myocyte destruction. Since verapamil (2 µmol/L) was ineffective, indicating that the CoCl₂ protection was not due to block of I_Ca,L, we tested whether the different action of these Ca²⁺ channel blockers was due to their differential effect on the PEL's K⁺ current (I_K), previously shown to participate in lymphocyte activation and cytotoxicity. In agreement with their protective efficacy, CoCl₂ but not verapamil blocked I_K in PELs, suggesting that this is the mechanism for the protection provided by CoCl₂. To support this notion, we tested the effect of the scorpion-derived peptide margatoxin (10 nmol/L), a specific K⁺ channel blocker in lymphocytes, on PEL-myocyte interaction and on PEL's I_K; margatoxin prevented PEL-induced cytotoxicity and also blocked I_K in PEL. Based on these findings, an alternative modality for attenuating CTL-induced lymphocytotoxicity is proposed.

Key Words: cytotoxic T lymphocytes • peritoneal exudate cytotoxic C lymphocytes • ventricular myocytes • heart transplant rejection • Ca²⁺ channel blockers

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