L-cis diltiazem attenuates intracellular Ca(2+) overload by metabolic inhibition in guinea pig myocytes.
We have previously demonstrated that treatment with L-cis diltiazem reduced cardiac infarct size in vivo. To examine the effect of L-cis diltiazem on Ca(2+) overload induced by ischemia/reperfusion, we used a model for Ca(2+) overload produced by metabolic inhibition in isolated guinea pig myocytes. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was quantified by fura-2 fluorescence microscopy and Ca(2+) overload was induced by inclusion of 1 microM of carbonyl cyanide m-chrolophenylhydrazone (CCCP) for 40 min treatment followed by washout for 30 min. This treatment caused a large [Ca(2+)](i) elevation as well as a sustained contracture of the cardiomyocytes. The increase was suppressed by 10 microM of 2-[2-[4-(4-nitrobenzyloxy) phenyl] ethyl] isothiourea methanesulphonate (KB-R7943), a specific inhibitor of the Na(+)/Ca(2+) exchanger, but not by nitrendipine (10 microM). L-cis Diltiazem (10 microM) attenuated the [Ca(2+)](i) increase, suggesting that L-cis diltiazem elicits a cardioprotective effect via attenuation of the [Ca(2+)](i) increase induced by metabolic inhibition and energy repletion.
Nishida
M
M
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Science, University of Tokyo, 3-1 Hongo 7-chome, Bunkyo-ku, Tokyo, Japan.
Urushidani
T
T
Sakamoto
K
K
Nagao
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D004110:Diltiazem / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D002121:Calcium Channel Blockers; D019831:Sodium-Calcium Exchanger; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D009532:Nickel; D009568:Nitrendipine; D009529:Nicardipine; D004110:Diltiazem; D013890:Thiourea; D002118:Calcium