Cardiotoxicity of calmidazolium chloride is attributed to calcium aggravation, oxidative and nitrosative stress, and apoptosis.
The intracellular calcium concentration ([Ca](i)) regulates cell viability and contractility in myocardial cells. Elevation of the [Ca](i) level occurs by entry of calcium ions (Ca(2+)) through voltage-dependent Ca(2+) channels in the plasma membrane and release of Ca(2+) from the sarcoplasmic reticulum. Calmidazolium chloride (CMZ), a subgroup II calmodulin antagonist, blocks L-type calcium channels as well as voltage-dependent Na(+) and K(+) channel currents. This study elaborates on the events that contribute to the cytotoxic effects of CMZ on the heart. We hypothesized that apoptotic cell death occurs in the cardiac cells through calcium accumulation, production of reactive oxygen species, and the cytochrome c-mediated PARP activation pathway. CMZ significantly increased the production of superoxide (O(2)(*-)) and nitric oxide (NO) as detected by FACS and confocal microscopy. CMZ induced mitochondrial damage by increasing the levels of intracellular calcium, lowering the mitochondrial membrane potential, and thereby inducing cytochrome c release. Apoptotic cell death was observed in H9c2 cells exposed to 25 microM CMZ for 24 h. This is the first report that elaborates on the mechanism of CMZ-induced cardiotoxicity. CMZ causes apoptosis by decreasing mitochondrial activity and contractility indices and increasing oxidative and nitrosative stress, ultimately leading to cell death via an intrinsic apoptotic pathway.
Kumar
Sandeep
S
National Centre for Cell Science, NCCS Complex, Pune University Campus, Ganeshkhind, Pune 411007, Maharashtra, India.
Kain
Vasundhara
V
Sitasawad
Sandhya L
SL
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002460:Cell Line; D002469:Cell Separation; D002712:Chlorides; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D007093:Imidazoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D000700:Analgesics; D002147:Calmodulin; D002712:Chlorides; D007093:Imidazoles; D013481:Superoxides; D009569:Nitric Oxide; C031938:calmidazolium; D045304:Cytochromes c; D002118:Calcium