Abstract
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.
Footnotes
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DOI: 10.1124/jpet.102.038331
- Abbreviations:
- HF
- heart failure
- LVP
- left ventricular pressure
- +dP/dtmax
- maximum velocity of pressure rise
- HR
- heart rate
- −dP/dtmax
- maximum velocity of pressure fall
- ED80
- dose increasing +dP/dtmax by 80%
- EDmax
- dose inducing the maximum increase in +dP/dtmax
- LD
- lethal dose
- DMSO
- dimethyl sulfoxide
- bpm
- beats per minute
- LVEDP
- left ventricular end diastolic pressure
- SBP
- systolic blood pressure
- Received May 9, 2002.
- Accepted July 3, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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