G. Haeusler et al., IN-VIVO EVIDENCE OF POSITIVE INOTROPISM OF EMD-57033 THROUGH CALCIUM SENSITIZATION, Journal of cardiovascular pharmacology, 29(5), 1997, pp. 647-655
The previous separation of the racemic cardiotonic thiadiazinone deriv
ative EMD 53 998 yielded two enantiomers with different pharmacologic
properties: EMD 57 033, a potent Ca2+ sensitizer with some residual ph
osphodiesterase III (PDE III) inhibition, and EMD 57 439, a pure PDE I
II inhibitor. Although numerous in vitro studies demonstrated the abil
ity of EMD 57 033 to increase the responsiveness of cardiac contractil
e proteins to Ca2+, in vivo evidence for such an action is lacking. Be
cause there is no possibility of directly proving Ca2+ sensitization i
n vivo, we attempted to exclude PDE III inhibition as a major contribu
ting component of the positive inotropic action of EMD 57 033. In anes
thetized rats, EMD 57 033 increased left ventricular (LV) first deriva
tive of change in systolic pressure over time (dP/dt max) without affe
cting blood pressure. In contrast, the PDE m-inhibitory enantiomer EMD
57 439 decreased blood pressure. The pattern of hemodynamic effects i
n anesthetized dogs revealed similar differences between EMD 57 033 an
d PDE inhibitors. Thus the increase in LVdP/dt max in response to EMD
57 033 was not accompanied by changes of heart rate and blood pressure
. As expected for PDE inhibitors, pimobendan and milrinone increased c
ardiac contractile force in dogs, concomitant, however, with tachycard
ia, hypotension, and a decrease in total peripheral resistance. When r
egional contractility was measured separately in two different areas o
f the dog myocardium, the positive inotropic action of the PDE inhibit
ors pimobendan and milrinone was antagonized by local coronary infusio
n of acetylcholine. The cardiotonic effect of the Ca2+ sensitizer EMD
57 033 was entirely resistant to inhibition by acetylcholine. In consc
ious dogs, beta-blockade markedly attenuated the increase in LVdP/dt m
ax produced by two different doses of the PDE III inhibitor EMD 57 439
. In contrast, a dose of EMD 57 033 equieffective in positive inotropi
c action with the lower dose of EMD 57 439 remained unaffected by <b t
au-blockade. We concluded (a) that EMD 57 033 increases cardiac contra
ctile force in two species in vivo, (b) that this action is independen
t of the cardiac cyclic adenosine monophosphate (AMP) system, (c) that
EMD 57 033 does not reduce blood pressure and increase heart rate, an
action indicative of PDE inhibition, and (d) that, on the basis of nu
merous previous in vitro findings, the mechanism of action of EMD 57 0
33, also in vivo, is consistent with sensitization of the cardiac myof
ibrils to Ca2+. Of special importance is the finding that this Ca2+ se
nsitizer at appropriate doses may be able to improve systolic function
without adverse effects on diastolic function, as indicated by a slig
ht decrease in left ventricular end-diastolic pressure.