Kenji Sakamoto1,#, Makoto Ishikawa2,
Keiko Koga2, Tetsuro Urushidani1 and Taku Nagao1,*
1Laboratory╩of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, The University of Tokyo,
Tokyo 113-0033, Japan
2Bioenergetics╩Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0130, Japan
#Present╩address: Laboratory of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan
*╩To whom reprint requests should be addressed.
Abstract: We determined the effect of l-cis diltiazem, the enantiomer of diltiazem (d-cis isoform), on the energy metabolism of isolated guinea pig hearts during ischemia-reperfusion. We used 31P-NMR to measure the high-energy phosphate content and intracellular pH (pHi) during global ischemia for 30╩min followed by reperfusion for 30╩min. Before ischemia, the left ventricular developed pressure (LVDP) was reduced less by 10╩mM l-cis diltiazem than by 3╩mM diltiazem or 500╩nM nifedipine. However, 10╩mM l-cis diltiazem preserved the intracellular ATP content during ischemia and reperfusion, reduced the end-diastolic pressure increase during ischemia and reperfusion, and restored LVDP after reperfusion. Nifedipine at 50╩nM, which reduced the LVDP more than 10╩mM l-cis diltiazem, showed no cardioprotective effect. Ten micromolar l-cis diltiazem and 3╩mM diltiazem, but neither 50 nor 500╩nM nifedipine, reduced the pHi decrease that occurred 25 or 30╩min after the onset of ischemia. Therefore, l-cis diltiazem has a cardioprotective effect on ischemic and reperfused myocardium and is less cardiodepressive than diltiazem and nifedipine. The effect of l-cis diltiazem during ischemia and reperfusion involves energy preservation, which is probably independent of its Ca2+-channel blocking action.
Keywords: l-cis Diltiazem, Nifedipine, Ischemia, Reperfusion