Effects of CP-060S, a novel Ca(2+) channel blocker, on oxidative stress in cultured cardiac myocytes.
The effect of (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4-one hydrogen fumarate (CP-060S), a novel Ca(2+) channel blocker, on hydrogen peroxide (H(2)O(2))-induced cytotoxicity was studied in cultured rat cardiac myocytes. The CP-060S effect was compared with that of CP-060R, an optical isomer of CP-060S with a less potent Ca(2+) channel blocking action than CP-060S. H(2)O(2) increased the release of lactate dehydrogenase from cardiac myocytes and decreased the formation of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) (MTT) formazan in cardiac myocytes (i.e., cytotoxic action). Both CP-060S (1 microM) and CP-060R (1 microM) attenuated to a similar extent the foregoing alterations induced by H(2)O(2). On the other hand, 1,3-dimethyl-2-thiourea (10 mM), a scavenger of both H(2)O(2) and hydroxyl radical, also attenuated the H(2)O(2)-induced cytotoxicity whereas diltiazem (10 microM) did not. In an experiment using electron spin resonance (ESR) with 5, 5-dimethyl-1-pyrroline N-oxide (DMPO), a spin-trapping agent, both CP-060S and CP-060R decreased the intensity of DMPO-hydroxyl radical signal concentration dependently. These results suggest that CP-060S protects cardiac myocytes from oxidative stress through its radical scavenging action.
Hara
A
A
Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan.
Suzuki
T
T
Hashizume
H
H
Shishido
N
N
Nakamura
M
M
Ushikubi
F
F
Abiko
Y
Y
D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000633:toxicity; D004110:Diltiazem / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity; D017665:Hydroxyl Radical / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D053778:Thiazolidines; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C115426:CP 060; C104781:CP 060S; D002121:Calcium Channel Blockers; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D016877:Oxidants; D010636:Phenols; D013844:Thiazoles; D053778:Thiazolidines; D017665:Hydroxyl Radical; C069977:2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxy; C038983:1,3-dimethylthiourea; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D004110:Diltiazem; D013890:Thiourea