RT Journal Article
SR Electronic
T1 Pharmacological Profile of the Novel Inotropic Agent  (<em>E</em>,<em>Z</em>)-3-((2-Aminoethoxy)imino)androstane-6,17-dione Hydrochloride (PST2744)
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 592
OP 600
DO 10.1124/jpet.102.038331
VO 303
IS 2
A1 Micheletti, R.
A1 Mattera, G. G.
A1 Rocchetti, M.
A1 Schiavone, A.
A1 Loi, M. F.
A1 Zaza, A.
A1 Gagnol, R. J. P.
A1 De Munari, S.
A1 Melloni, P.
A1 Carminati, P.
A1 Bianchi, G.
A1 Ferrari, P.
YR 2002
UL http://jpet.aspetjournals.org/content/303/2/592.abstract
AB 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 &lt; 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 &lt; 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. The American Society for Pharmacology and Experimental Therapeutics