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Vol. 303, Issue 2, 592-600, November 2002
Prassis Sigma-Tau Research Institute, Settimo Milanese, Italy
(R.M., A.S., S.D.M, P.M., P.F.); Sigma-Tau R & D, Pomezia, Italy
(G.G.M., M.F.L., P.C.); Department of Biotechnologies and Biosciences,
Università degli Studi di Milano, Bicocca, Italy (M.R., A.Z.);
Centre National de la Recherche Scientifique, Montpellier, France
(J.P.G.); and Università Vita e Salute, Milan, Italy (G.B.)
The novel Na+/K+-ATPase inhibitor
(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione
hydrochloride (PST2744) was characterized for its inotropic and toxic
properties. Inhibition potency on dog kidney
Na+/K+-ATPase was comparable (0.43 µM) to
that of digoxin (0.45 µM). PST2744 concentration-dependently
increased force of contraction in guinea pig atria and twitch amplitude
in isolated guinea pig myocytes; in the latter, aftercontractions
developed significantly less than with digoxin. Intravenous infusion of
0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted an immediate
and long-lasting inotropic effect (ED80 of 1.89 ± 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose
of 18 mg/kg. Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED80 of 0.32 mg/kg) caused lethal arrhythmias at
a cumulative dose of 0.81 mg/kg. At a higher rate (0.4 mg/kg/min),
PST2744 induced lethal arrhythmias, with a lethal
dose/ED80 ratio significantly greater than digoxin
(20.2 ± 6.3 versus 3.23 ± 0.55, p < 0.05). Decay of the inotropic effect (t1/2,
min) was significantly faster for PST2744 (6.0 ± 0.39) than for
digoxin (18.3 ± 4.5, p < 0.05). In
anesthetized dogs, PST2744 dose-dependently increased maximum velocity
of pressure rise (+dP/dtmax) in the range 32 to 500 µg/kg i.v. and was safer than digoxin. In conscious dogs with a healed myocardial infarction, PST2744 significantly increased resting values
of +dP/dtmax, left ventricular pressure, and SPB, and
increased +dP/dtmax throughout treadmill exercise while
reverting the increase in left ventricular end diastolic pressure seen
in control animals. Digoxin significantly decreased basal heart rate,
while not affecting the hemodynamic response to exercise. Thus, PST2744
represents a new class of Na+/K+-ATPase
inhibitors endowed with inotropic activity comparable with that of
digitalis but having greater safety.
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