Hong Ma, Hiroko Hashizume(*), Akiyoshi Hara, Kazuto Yazawa and Yasushi
Abiko
Department of Pharmacology, Asahikawa Medical College, Nishikagura 4-5,
Asahikawa 078-8510, Japan
(*) To whom correspondence should be addressed.
Abstract: We examined the effects of quinaprilat, an active metabolite
of quinapril (an angiotensin converting enzyme (ACE) inhibitor) on the increase
in intracellular concentration of Ca2+ ([Ca2+]i) (Ca2+-overload)
induced by lysophosphatidylcholine (LPC) in isolated rat cardiomyocytes.
LPC (15 microM) produced Ca2+-overload with a change in cell-shape
from rod to round. Quinaprilat but not quinapril at 20 or 50 microM attenuated
the LPC-induced increase in [Ca2+]i and the change in cell-shape
in a concentration-dependent manner. Since quinaprilat has an inhibitory
action on ACE and quinapril has practically no inhibitory action on ACE,
it is likely that the inhibitory action of quinaprilat on ACE is necessary
for the protective effect of the drug against LPC-induced changes. We therefore
examined the effects of enalapril (another ACE inhibitor with the weak inhibitory
action on ACE) and enalaprilat (an active metabolite of enalapril with an
inhibitory action on ACE) on the LPC-induced changes. Both enalapril and
enalaprilat attenuated the LPC-induced Ca2+-overload, suggesting
that the inhibitory action on ACE may not mainly contribute to the protective
effect of ACE inhibitors against LPC-induced Ca2+-overload. This
suggestion was supported by the fact that neither ACE (0.2 U/ml) nor angiotensin
II (0.1 - 100 microM) increased [Ca2+]i in isolated cardiomyocytes.
Furthermore, application of bradykinin (0.01 - 10 microM) did not enhance
the protective effect of quinaprilat against LPC-induced changes. LPC also
increased release of creatine kinase (CK) from the myocyte markedly, and
quinaprilat but not quinapril attenuated the LPC-induced CK release. Unexpectedly,
both enalapril and enalaprilat did not attenuate the LPC-induced CK release.
Neither quinapril nor quinaprilat changed the critical micelle concentration
of LPC, suggesting that these drugs do not directly bind to LPC. We conclude
that quinaprilat attenuates the LPC-induced increase in [Ca2+]i,
and that the protective effect of quinaprilat on the LPC-induced change
may not be related to a decrease in angiotensin II production or an increase
in bradykinin production.
Keywords: Ca2+-overload, Lysophosphatidylcholine, Cardiomyocyte,
Angiotensin converting enzyme inhibitor, Creatine kinase