Yf. Xiao et al., Mechanism of suppression of cardiac L-type Ca2+ currents by the phospholipase A(2) inhibitor mepacrine, EUR J PHARM, 399(2-3), 2000, pp. 107-116
Phospholipase A(2) plays a crucial role in the release of arachidonic acid
(AA) from membrane phospholipids and in myocardial injury during ischemia a
nd reperfusion. Mepacrine, a phospholipase A(2) inhibitor, has been shown t
o protect the heart from ischemic injury. In order to examine the mechanism
of this protection, we investigated the effects of mepacrine on the L-type
Ca2+ current (I-Ca,I-L) in rat single ventricular myocytes. Extracellular
application of mepacrine significantly inhibited I-Ca,I-L in a tonic- and u
se-dependent manner. The inhibition was also concentration-dependent with a
n IC50 of 5.2 mu M. Neither the activation nor the steady-state inactivatio
n of I-Ca,I-L was altered by mepacrine. The mepacrine-induced inhibition of
I-Ca,I-L was reversible after washout of the inhibitor. Addition of 1 mu M
AA partially reversed the mepacrine-induced inhibition of I-Ca,I-L. Intrac
ellular dialysis, with 2 mM cAMP, significantly increased I-Ca,I-L but did
not prevent the mepacrine-induced inhibition of I-Ca,I-L. In addition, extr
acellular application of isoproterenol or membrane permeable db-cAMP did no
t reverse the mepacrine-induced inhibition of I-Ca,I-L. Biochemical measure
ment revealed that incubation of ventricular myocytes with mepacrine signif
icantly reduced intracellular cAMP levels. The mepacrine-induced reduction
of cAMP production was abolished by addition of AA. Our results demonstrate
that mepacrine strongly inhibits cardiac I-Ca,I-L. While mepacrine is a ph
ospholipase A, inhibitor and reduces cAMP production, its inhibitory effect
on I-Ca,I-L mainly results from a direct block of the channel. Therefore,
we speculate that the protective effect of mepacrine during myocardial isch
emia and reperfusion mostly relates to its blockade of Ca2+ channels. (C) 2
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