Amrinone enhances myocardial contractility and improves left ventricular diastolic function in conscious and anesthetized chronically instrumented dogs

Abstract

Background: Volatile anesthetics depress left ventricular mechanical performance in vivo by altering intracellular calcium regulation. Although amrinone has been shown to reverse the negative inotropic effects of volatile anesthetics, the actions of amrinone on anesthetic-induced diastolic dysfunction are unknown. This investigation examined and compared the direct effects of amrinone on left ventricular systolic and diastolic function in conscious and anesthetized dogs. Methods: Experiments were conducted in the presence of pharmacologic blockade of the autonomic nervous system, because autonomic activity may influence the hemodynamic actions of volatile anesthetics and amrinone in vivo. Three groups, comprising a total of 27 experiments, were conducted using 9 dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dt, subendocardial segment length, diastolic coronary blood flow velocity, and cardiac output. Myocardial contractility was evaluated using the preload recruitable stroke work relationship slope (M(w)). Diastolic function was characterized by a time constant of isovolumic relaxation (τ), a regional chamber stiffness constant (K(p)), and maximum segment lengthening velocity during rapid ventricular filling (dL/dt(max)). On three separate days, an amrinone bolus of 1 mg/kg, followed by an infusion at 10, 20, 40, or 80 μg · kg-1 · min-1, was administered. Hemodynamics and ventricular pressure-segment length loops and waveforms were recorded after a 15-min equilibration at each dose in the conscious state or during isoflurane or halothane anesthesia (1.25 MAC). Results: In conscious dogs, amrinone significantly increased myocardial contractility in a dose-dependent manner (M(w) of 65 ± 8 to 108 ± 10 mmHg at the high dose). Amrinone also shortened isovolumic relaxation (τ of 32.7 ± 2.1 to 24.8 ± 0.9 ms at the high dose) and enhanced rapid ventricular filling (dL/dt(max) of 34.8 ± 1.2 to 45.1 ± 2.3 mm/s at the high dose) in a dose-related fashion. In addition, amrinone reduced regional chamber stiffness (K(p) of 0.49 ± 0.09 to 0.31 ± 0.08 mm/s at the high dose) in conscious dogs. Amrinone also enhanced left ventricular systolic (increase in M(w)) and diastolic function (decreases in τ and K(p) and increases in dL/dt(max)) when this drug was administered to dogs anesthetized with isoflurane or halothane. Conclusions: Amrinone produced positive inotropic and lusitropic effects in both conscious and anesthetized dogs with autonomic nervous system blockade. These results indicate that amrinone-induced improvement of left ventricular performance are related to actions in diastole, as well as systole.