Effects of CP-060S, a novel Ca2+ channel blocker, on oxidative stress in cultured cardiac myocytes

The effect of (-)-(S)-2-[3,5-bis(1,1-dimethylethyl)-4-hyroxyphenyl]-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)-ethyl]amino]propyl]-1,3-thiazolidin-4-one hydrogen fumarate (CP-060S), a novel Ca2+ channel blocker, on hydrogen peroxide (H2O2)- 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 Ca2+ channel blocking action than CP-060S. H2O2 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 mu M) and CP-060R (1 mu M) attenuated to a similar extent the foregoing alterations induced by H2O2. On the otherhand, 1,3-dimethyl-2-thiourea (10 mM), a scavenger of both H2O2 and hydroxyl radical, also attenuated the H2O2-induced cytotoxicity whereas diltiazem(10 mu M) 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. (C) 1999 Elsevier Science B.V. All rights reserved.