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Vol. 288, Issue 1, 316-325, January 1999
Molecular and Cellular Physiology, University of Cincinnati
(P.B., R.J.P.) and
Orion Pharmaceutical Research, Espoo, Finland
(H.H.)
Levosimendan is a pyridazinone-dinitrile derivative belonging to
a new class of cardiac inotropic drugs, Ca++ sensitizers.
Levosimendan is also a vasodilator both in vitro and in vivo, but its
mechanism is not well understood. The cardiac target protein of
levosimendan, troponin C, is a Ca++-binding EF-hand
protein. This raises the possibility that levosimendan may also
interact with smooth muscle EF-hand proteins, such as, calmodulin, the
regulatory myosin light chains, or S100 proteins. We investigated the
effects of levosimendan on [Ca++]i, and force
in porcine coronary arteries, with receptor-mediated (U46619) or KCl
stimulation. At high levels of stimulation, levosimendan decreased
force without changing or increasing [Ca++]i,
measured with the Ca++-sensitive fluorescent probe
fura-2 in the intact artery. With lower levels of U46619,
levosimendan (1 µM) lowered force by 70% and reduced
[Ca++]i by 38%. The relationship between
force and [Ca++]i for KCl stimulation are
significantly rightward shifted, indicating Ca++
desensitization by levosimendan. In contrast, the phosphodiesterase III
inhibitor, milrinone, does not shift the force-Ca++
relations but elicits relaxation via lowering
[Ca++]i. There was little change in
pHi, indicating that the Ca++ desensitization
by levosimendan was not attributable to decreasing pHi.
Levosimendan relaxes coronary arteries and lowers
[Ca++]i by mechanisms different than
milrinone. Our results indicate a lowering of
[Ca++]i by levosimendan consistent with
opening of potassium channels and a relaxation that is independent of
[Ca++]i. Our evidence points to a novel
mechanism that might involve the direct effect of levosimendan on the
smooth muscle contractile or regulatory proteins themselves.
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