Kenji Sakamoto1,#, Makoto Ishikawa2,
Keiko Koga2, Tetsuro Urushidani1 and Taku Nagao1,*
1Laboratoryﾊof Pharmacology and Toxicology, Graduate School
of Pharmaceutical Sciences, The University of Tokyo,
Tokyo 113-0033, Japan
2BioenergeticsﾊResearch Center, Tokushima Research Institute,
Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0130, Japan
#Presentﾊaddress: Laboratory of Molecular
Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo
108-8641, Japan
*ﾊ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ﾊmin followed by reperfusion for 30ﾊmin. Before
ischemia, the left ventricular developed pressure (LVDP) was reduced less
by 10ﾊmM l-cis diltiazem than by 3ﾊmM
diltiazem or 500ﾊnM nifedipine. However, 10ﾊ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ﾊnM,
which reduced the LVDP more than 10ﾊmM l-cis
diltiazem, showed no cardioprotective effect. Ten micromolar l-cis
diltiazem and 3ﾊmM diltiazem, but neither 50
nor 500ﾊnM nifedipine, reduced the pHi decrease that occurred
25 or 30ﾊ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