Pharmacological Profile of the Novel Inotropic Agent (E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione Hydrochloride (PST2744)

Abstract

The novel Na ϩ /K ϩ -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 ϩ /K ϩ -ATPase was comparable (0.43 M) to that of digoxin (0.45 M). 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 (ED 80 of 1.89 Ϯ 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; ED 80 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/ED 80 ratio significantly greater than digoxin (20.2 Ϯ 6.3 versus 3.23 Ϯ 0.55, p Ͻ 0.05). Decay of the inotropic effect (t 1/2 , min) was significantly faster for PST2744 (6.0 Ϯ 0.39) than for digoxin (18.3 Ϯ 4.5, p Ͻ 0.05). In anesthetized dogs, PST2744 dose-dependently increased maximum velocity of pressure rise (ϩdP/dt max ) in the range 32 to 500 g/kg i.v. and was safer than digoxin. In conscious dogs with a healed myocardial infarction, PST2744 significantly increased resting values of ϩdP/dt max , left ventricular pressure, and SPB, and increased ϩdP/dt max 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 ϩ /K ϩ -ATPase inhibitors endowed with inotropic activity comparable with that of digitalis but having greater safety.Improvement of heart failure (HF) treatment remains a major medical challenge for the coming years. Despite achievement of considerable progress during the last two decades, none of the available therapeutic agents is fully satisfactory, and HF remains a disease with a poor prognosis (Kannel, 2000). The goal of ameliorating quality of life, exercise capability, and survival is only partially met by angiotensin-converting enzyme inhibitors, diuretics, vasodilators, glycosides, and ␤-blocking agents, regardless of their being used in combined therapy (Consensus Recommendations for the Management of Chronic Heart Failure, 1999). Therefore, the need still remains for novel drugs able to increase workload tolerance and to reduce morbidity and mortality. Worsening of survival found with chronic administration of inotropic agents that increase intracellular cAMP (phosphodiesterase inhibitors and sympathomimetic amines) (The Xamoterol in Severe Heart Failure Study Group, 1990;Packer et al., 1991;Cohn et al., 1998) and the well known arrhythmogenic effects of cardiac glycosides have led to the general view that drug-i...

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

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Istaroxime Inhibits Motility and Down-Regulates Orai1 Expression, SOCE and FAK Phosphorylation in Prostate Cancer Cells

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Emerging Therapies for Heart Failure

“…It has a proposed mechanism of action that involves inhibition of sodium-potassium adenosine triphosphatase (Na-K ATPase) activity at the sarcolemma leading to an increase in cytosolic calcium and stimulation of sarcoplasmic reticulum calcium ATPase isoform 2 (SERCA2), leading to its rapid sequestration back into the sarcoplasmic reticulum during diastole [70]. The impact of istaroxime on calcium cycling in the cardiomyocyte would be expected to have favorable effects on both inotropic and lusitropic properties in the failing heart.…”

“…The impact of istaroxime on calcium cycling in the cardiomyocyte would be expected to have favorable effects on both inotropic and lusitropic properties in the failing heart. In fact, in animal models, istaroxime has been reported to improve systolic and diastolic function without increasing myocardial oxygen consumption [70][71][72]. The dose dependent effects of istaroxime on LV ejection fraction in an animal model of heart failure are depicted in Figure 7.6.…”