Calcium channel blockers induce thymic apoptosis in vivo in rats.
We investigated the in vivo effect of structurally different calcium channel blockers (CCB) on rat thymus. Administration of verapamil (40 mg/kg ip), diltiazem (90 mg/kg ip), nifedipine (15 mg/kg ip), or nicardipine (10 mg/kg ip) induced apoptotic indices of 4.3, 4.0, 2.0, and 6.5, respectively, compared to 0.5 in the saline-treated control rats. Apoptosis was assessed by morphology and the apoptotic index was calculated using a computer-assisted image analyzer. Diltiazem had a rapid and substantial effect as evidenced by apoptosis at 1.5 hr and a 36% decrease in thymus weight by 24 hr. We were uncertain about the mechanisms by which CCB induced thymic apoptosis in vivo since in vitro studies have shown that increases in intracellular calcium cause apoptosis and that CCB prevent apoptosis. We sought insight into the mechanism by evaluating potential and known in vivo effects of these drugs. Neither verapamil nor diltiazem was found to elevate serum cortisol levels, a known trigger for apoptosis. Hypotension, a known response to CCB, does not appear to be causal factor since the potent hypotensive agent sodium nitroprusside (10 microg/kg, iv) did not cause a significant increase in thymic apoptosis. Calcium signaling may be important since the calmodulin antagonist chlorpromazine (60 mg/kg ip) was found to induce a 15-fold increase in apoptosis. Our observations suggest that calcium signaling is necessary for the survival of the T lymphocytes in the thymus.
Balakumaran
A
A
Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605, USA.
Campbell
G A
GA
Moslen
M T
MT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity*; D002746:Chlorpromazine / Q000008:administration & dosage / Q000633:toxicity; D004110:Diltiazem / Q000008:administration & dosage / Q000633:toxicity; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006854:Hydrocortisone / Q000097:blood; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D007274:Injections, Intraperitoneal; D008297:Male; D008854:Microscopy, Electron; D009529:Nicardipine / Q000008:administration & dosage / Q000633:toxicity; D009543:Nifedipine / Q000008:administration & dosage / Q000633:toxicity; D009599:Nitroprusside / Q000008:administration & dosage / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D014700:Verapamil / Q000008:administration & dosage / Q000633:toxicity
D002121:Calcium Channel Blockers; D018492:Dopamine Antagonists; D009599:Nitroprusside; D014700:Verapamil; D009529:Nicardipine; D004110:Diltiazem; D009543:Nifedipine; D002746:Chlorpromazine; D006854:Hydrocortisone