Calcium channel blockers modify electrophysiological effects induced by lytic granules from cytotoxic T lymphocytes in guinea pig ventricular myocytes.
Damage to myocytes by infiltrating cytotoxic lymphocytes, containing lytic granules and the pore-forming protein, perforin, thereof, probably contribute to the immunological rejection of the transplanted heart, to autoimmune diseases and possibly to congestive heart failure associated with myocarditis. In the present study we investigated whether electrophysiological and morphological changes induced in guinea pig ventricular myocytes by lytic granules extracted from cytotoxic T lymphocytes, are modified by L-type Ca++ channel blockers. The organic blockers, verapamil (2 microM) and nisoldipine (500 microM) were unable to prevent or inhibit any of the deleterious effects of lytic granule on action potential and myocyte morphology, and the granule-induced increase in the membrane current measured at the end of 300-msec clamp pulse. In contrast, the inorganic blockers CoCl2 (3 mM) and NiCl2 (4 mM) provided considerable protection against the granule actions mentioned above, but an equally potent Ca++ blocker, CdCl2 (3 mM) was ineffective. The protective efficacy of CoCl2 (and probably that of NiCl2) was most likely due to its capacity to reduce or block the generation by lytic granules/perforin of large-conductance (approximately 1400 pS) channels responsible for inducing Ca++ overload and cell destruction. We consider these studies of importance because they direct further studies aimed at developing effective means for attenuating cytotoxic T lymphocyte-induced tissue damage, for example during transplant rejection or in autoimmune diseases.
Binah
O
O
Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine-Technion, Haifa, Israel.
Berke
G
G
Rosen
D
D
Hoffman
B F
BF
D000200:Action Potentials; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002712:Chlorides / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000276:immunology; D006461:Hemolysis; D066298:In Vitro Techniques; D015737:Nisoldipine / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002712:Chlorides; D002104:Cadmium; D003035:Cobalt; D015737:Nisoldipine; D014700:Verapamil; C018021:cobaltous chloride; D019256:Cadmium Chloride