Hemodynamic Assessment of Amrinone

SUMMARYThe cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, waa investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-1000 /ig/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 /ig/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na + ,K + -activated ATPase. Ore Res 45: 666-677, 1979 A LARGE number of agents have positive inotropic effects on the heart. However, of these, only two classes of compounds have been found to be useful in the treatment of heart failure in man. The cardiac glycosides have enjoyed a valued position for nearly 200 years in spite of the fact that they have a narrow therapeutic range, and digitalis intoxication is one of the most common drug-induced adverse reactions in this country (Mason et al., 1971;Beller et al., 1971;Doherty and Kane, 1975). The catecholamines have limitations in that they are arrhythmogenic, are chronotropic, have a short duration of action, and cannot be given orally (Goldberg, 1968). Dopamine (Goldberg, 1974;Beregovich et al., 1974) and the synthetic catecholamine, amine dobutamine (Tuttle and Mills, 1975;Goldberg et al, 1977), both of which have been introduced recently for clinical use, suffer from most of the same drawbacks as the older catecholamines. Other inotropic agents, such as glucagon (Farah and Tuttle, 1960;Glick et al., 1968) has proved of value in the management of congestive heart failure (Cohn and Franciosa, 1977;Mehta, 1977).The development of an orally active non-catechol and non-glycoside cardiotonic agent has been the goal of this laboratory for several years (Alousi and Farah, 1975;Alousi et al., 1978;Farah and Alousi, 1978). Amrinone (Win 40680), a 5-amino-3,4'-bipyridine-6(lH)-one, is a novel chemical entity with rather unique cardiac inotropic properties Farah and Alousi, 1978). In this report, the action of amrinone on the heart is studied in several models, and in light of these res...

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“…Preliminary results in patients (Benotti et al, 1978;Le Jemtel et al, 1979) have confirmed our findings in the dog.…”

Section: Discussionsupporting

confidence: 87%

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Alousi¹,

Farah²,

Lesher³

et al. 1979

Circulation Research

219

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“…'F'6 To some extent, this discrepancy can be explained by the influence of cardiac loading conditions on peak positive left ventricular dP/dt. 7 Amrinone, in large doses, produces potent direct arteriolar and venous dilatation that markedly reduces left ventricular filling pressure. This may, therefore, result in a fall in peak positive left ventricular dP/dt that tends to offset the rise produced by the positive inotropic action of the drug.…”

Section: Discussionmentioning

confidence: 99%

Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure.

Gage¹,

Rutman²,

Lucido³

et al. 1986

Circulation

165

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The effects of amrinone, dobutamine, and a combination of the two drugs on peak positive left ventricular dP/dt and left ventricular performance were evaluated in 11 patients with chronic congestive heart failure. When administered alone, both dobutamine (10.9 gg/kg/min) and intravenous amrinone (1.9 mg/kg/min) significantly increased left ventricular dP/dt and performance. When compared with dobutamine alone, the addition of amrinone resulted in further increases in left ventricular dP/dt and cardiac index (to 1319 ± 419 from 1202 ± 376 mm Hg/sec, p < .002, and to 3.56 ± 0.78 from 3.04 ± 0.67 liters/min/m2, p < .01, respectively). The combination also induced a further reduction in left ventricular end-diastolic pressure (to 15.3 ± 11.3 from 18.2 ± 10.3 mm Hg, p < .05) when compared with amrinone alone. The combination of dobutamine and amrinone increased heart rate slightly when compared with either drug alone, but did not further reduce systemic arterial pressure when compared with amrinone alone. The dose-response curve of left ventricular dP/dt and performance during titration of dobutamine with and without the addition of intravenous amrinone was evaluated in seven patients. The addition of amrinone to any dose of dobutamine produced higher cardiac index and lower systemic vascular resistance than dobutamine or amrinone alone. Thus, when compared with dobutamine alone in patients with chronic congestive heart failure, the addition of intravenous amrinone to dobutamine results in an additive improvement in left ventricular performance throughout the dose range. Circulation 74, No. 2, 367-373, 1986. DOBUTAMINE is a synthetic catecholamine that directly stimulates myocardial /,-adrenergic receptors.It has been used extensively to improve myocardial contractility and ventricular performance in patients with acute left ventricular dysfunction or decompensated congestive heart failure.", 2 Dobutamine is usually well tolerated. Through its effects on cardiac mechanics and hemodynamics, it has the potential to alter myocardial oxygen utilization (MVO2) in several different ways. By increasing contractility and heart rate, it may increase MVO2, but the simultaneous reduction in wall tension tends to lower oxygen use. In some situations the stimulation of contractility and heart rate may outweigh the reduction in wall tension to

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“…The study population consisted of 11 consecutive patients with New York Heart Association functional class III or IV congestive heart failure despite optimal standard therapy with digitalis, diuretics, and vasodilators in all cases (table 1). The cause of congestive heart failure was coronary artery disease in six patients and dilated cardiomyopathy in five.…”

Section: Methodsmentioning

confidence: 99%

“…All vasodilators were withheld for at least 36 hr before the time of study, and digitalis and diuretics were withheld on the morning of catheterization. In the cardiac catheterization laboratory, catheters were positioned with patients under local lidocaine (1%) anesthesia as follows: (1) the difference between paired femoral and pulmonary arterial oxygen contents. The following standard formulas were used for derived hemodynamic variables: systemic vascular resistance (SVR, dyne-sec-cnm5) = 79.9 (MP -RA)/CO; pulmonary vascular resistance (PVR, dyne-sec-cmn5) = 79.9 (PA -PCW)/CO; stroke volume index (SVI, ml/beat/M2) = CI/HR: and stroke work index (SWI, g-m/m2) SVI (MP-LVEDP) (0.0136), where MP = mean arterial pressure, RA = mean right atrial pressure, PA = mean pulmonary arterial pressure, PCW = mean pulmonary capillary wedge pressure, LVEDP = left ventricular end-diastolic pressure (all pressures reported in mm Hg), HR = heart rate, CO = cardiac output (liters/min), and CI = cardiac index (liters/min/m2).…”

Section: Methodsmentioning

confidence: 99%

Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique.

Ludmer¹,

Wright²,

Arnold³

et al. 1986

Circulation

123

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To determine the relative contributions of milrinone's positive inotropic and vasodilator actions in patients with severe congestive heart failure, the drug was administered by constant infusion directly into the left main coronary artery of 11 patients with New York Heart Association functional class III or IV heart failure. Intracoronary infusion of milrinone at rates up to 50 ,ug/min had no effect on mean arterial pressure or systemic vascular resistance but resulted in dose-related increases in peak positive dP/dt ( + 21%), stroke volume index ( + 18%), and stroke work index ( + 21%) and decreases in heart rate (-33%), mean right atrial pressure (-25%), and left ventricular end-diastolic pressure (-17%). In eight patients, intravenous administration (75 jig/kg) after the intracoronary infusion resulted in significant decreases in mean arterial pressure (-14%) and systemic vascular resistance ( 40%), further increase in stroke volume index compared with intracoronary administration, and further decreases in mean right atrial and left ventricular end-diastolic pressures compared with intracoronary administration. These data indicate that milrinone exerts both positive inotropic and vasodilator actions that contribute significantly to the drug's overall hemodynamic effect.

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Hemodynamic Assessment of Amrinone

Cited by 379 publications

References 2 publications

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure.

Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique.

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