Comparison of the calcium entry and calcium overload blocking properties of R71811 and flunarizine.
The effects of several calcium antagonists on cell death induced by A23187 were studied. Furthermore, R71811, 1-[Bis(4-fluorophenyl)methyl-4-[(4-methoxyphenyl)- carbamoylmethyl-trans-2,5-dimethyl-piperazine has been evaluated as a calcium overload blocker and compared to flunarizine. The viability of cultured glial cells was decreased by incubation with the calcium ionophore, A23187. The cytotoxicity of A23187 was reduced by flunarizine and cinnarizine at 10 mumol/l; nicardipine, nifedipine, and verapamil, but not diltiazem, reduced cytotoxicity at 100 mumol/l. N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide (W-7) and trifluoperazine did not reduce cytotoxicity and trifluoperazine enhanced cytotoxicity at 100 mumol/l. Leupeptin reduced cytotoxicity at 100 mumol/l. [8-(N,N-dimethylamino)-octyl-3,4,5- trimethoxybenzoate] (TMB-8) showed no effect. The results indicate that flunarizine, a recognized calcium overload blocker, was most effective in inhibiting the A23187-induced cytotoxicity and that calcium entry blockade does not appear to be implicated in the cytoprotective effect. R71811 inhibited A23187 cytotoxicity at similar concentrations to flunarizine. R71811, as well as flunarizine, also inhibited erythrocyte crenation induced by A23187. Although R71811 showed a relaxant effect in isolated rat aorta contracted by high potassium, its activity was less than that of flunarizine (IC50 values, 4.1 and 0.045 mumol/l, respectively). On the other hand, R71811 and flunarizine showed similar inhibitory effects on A23187-induced contractions (IC50 values, 14 and 11 mumol/l, respectively). The results indicate that R71811 has a similar protective effect against A23187-induced cytotoxicity but only weak calcium entry blocking action in comparison to flunarizine.
Matsui
Y
Y
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Yamagami
I
I
Hirai
K
K
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005444:Flunarizine / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D002121:Calcium Channel Blockers; D010879:Piperazines; C067179:R 71811; D000001:Calcimycin; D004533:Egtazic Acid; D005444:Flunarizine; D002118:Calcium