Hemodynamic Effects of a New Inotropic Compound, PST-2744, in Dogs With Chronic Ischemic Heart Failure

Abstract

Inotropic agents for acute decompensated heart failure are associated with a lack of efficacy or increased mortality. New compounds are needed to support patients with acute exacerbations of heart failure. This study examined the hemodynamic effects of a new inotropic agent (PST-2744) in dogs with chronic ischemic heart failure. Eight mongrel dogs at low risk for postmyocardial infarction (MI) sudden death entered the protocol. Dogs were studied after ischemic left ventricular dysfunction was induced by repeated injections of latex microspheres into the circumflex artery until the ejection fraction reached 35%. Hemodynamic parameters were measured at baseline and peak drug effect (PST-2744 5 microg.kg-1.min-1). In 5 animals, PST-2744 effects were compared with dobutamine. Heart rates, PR intervals and QT intervals were unchanged following PST-2744 administration. PST-2744 increased contractility (+dP/dt) by 56% from 1881 +/- 282 mm Hg/s to 2939 +/- 734 mm Hg/s (P < 0.01). The inotropic effect of PST-2744 was equal to that produced by 5-microg.kg-1.min-1 dobutamine (56% increase in +dP/dt), but peak heart rates were significantly higher with dobutamine (129 +/- 24 bpm PST-2744 versus 160 +/- 6 bpm 5-microg.kg-1.min-1 dobutamine, P < 0.002). No arrhythmias or conduction delays were seen with either compound. PST-2744 is an effective inotropic agent without positive chronotropic effect in subjects with stable moderate left ventricular dysfunction.

Attenuation of changes in Gi‐proteins and adenylyl cyclase in heart failure by an ACE inhibitor, imidapril

“…Previous observations have indicated attenuated cardiac function in CHF subsequent to myocardial infarction [24,27,28] and depressed heart function has been also reported in other animal models of heart failure [33,34] and failing human heart [35,36]. Since AC serves as the effector of β-AR signal pathway and amplifies heart function by increasing the formation of cAMP, a decrease in the basal AC activity can thus cause decreased accumulation of cAMP, leading to depressed heart function.…”

Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent

“…The combined mechanism of istaroxime allows for cytosolic calcium accumulation during systole (inotropic response), as well as rapid sequestration of calcium during diastole and myocardial relaxation (lusitropic response) (9,10). In the animal model, istaroxime improves systolic and diastolic function without increasing myocardial oxygen consumption (11,12). In chronic heart failure (HF), istaroxime is relatively safe in doses up to 5 g/kg/min (13).…”

Istaroxime in Heart Failure

“…Significant reductions in left ventricular end-diastolic pressure and end-diastolic wall stress, as well as increased deceleration time of early mitral inflow velocity, have also been reported (10). Istaroxime and dobutamine have been directly compared in a canine model of chronic ischemic heart failure (11). The change in dP/dt max during treatment was equivalent between the 2 agents (ϩ51%); however, the peak heart rate was significantly lower with istaroxime.…”

“…The drug shows unique mechanisms of action that are independent of increased levels of myocardial cyclic adenosine monophosphate. Unlike dobutamine or milrinone, this agent decreases heart rate, shortens QT C interval, and has no demonstrated pro-arrhythmic effects (11,12). It can acutely lower filling pressures and, at higher doses, improves both cardiac output and lusitropic function.…”