denopamine and Cardiomyopathies

Influence of cardiotonic agents on the prognosis of heart failure depends on the individual therapeutic agents, and favorable and unfavorable effects of these agents have been reported in clinical trials. We studied the effect of the cardiotonic agent denopamine on the life span of cardiomyopathic hamsters (BIO 14.6 strain) in the heart failure period. Non-treated hamsters started to die at 40 weeks of age, and their survival rate decreased to 23.8% at the age of 65 weeks. Hamsters treated with denopamine (400 ppm in diet) from 36 weeks of age did not die until the age of 52 weeks, except in cases of accidental death. The survival rate of this group at 65 weeks of age was about 40%. Survival rates of these 2 groups were significantly different (P < 0.05) when animals with accidental death were excluded. To elucidate the mechanism of the effect of denopamine, we performed several experiments after dietary treatment with denopamine for 4 to 6 weeks from 37 weeks of age. Denopamine treatment lowered plasma levels of noradrenaline and dopamine (P < 0.05), but affected neither the cardiac contractility nor the beta-adrenoceptor density. In summary, denopamine significantly decreases the mortality of cardiomyopathic hamsters. Its effect to lower the plasma catecholamine levels may be responsible for the beneficial effect of denopamine.

Topics: Adrenergic beta-1 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Pressure; Cardiomyopathies; Catecholamines; Cricetinae; Ethanolamines; Heart Function Tests; Heart Rate; Life Expectancy; Male; Organ Size; Papillary Muscles; Survival Rate

A new hydroxybenzyl alcohol derivative TA-064 exerts a positive inotropic action in experimental preparations. To assess the acute effects in man, we made a cardiac catheterization study of the hemodynamic responses to TA-064 (20 mg and/or 40 mg given orally) in eleven patients with refractory heart failure due to cardiomyopathy (nine patients with dilated cardiomyopathy and one with amyloidosis). All patients were already receiving full digitalis and diuretics therapy. The following statistically significant (P less than 0.05-0.01) effects were noted: Upon administration of 20 mg of the drug, the cardiac index (CI) increased from a mean +/- 1 SD of 1.6 +/- 0.4 to 2.1 +/- 0.6 l/min/m2; pulmonary capillary wedge pressure (PCW) fell from 25 +/- 5 to 21 +/- 5 mm Hg; right atrial pressure (RA) fell from 12 +/- 3 to 10 +/- 4 mm Hg. In contrast, when 40 mg TA-064 were administered orally, the CI increased from 1.7 +/- 0.4 to 2.4 +/- 0.9 l/min/m2; PCW fell from 25 +/- 8 to 20 +/- 6 mm Hg; pulmonary arterial mean pressure fell from 35 +/- 11 to 29 +/- 9 mm Hg. Neither systemic arterial mean pressure nor heart rate increased. No toxicity was observed. The plasma concentration of TA-064 increased dose-dependently and reached a peak value 0.5-1.5 h after oral administration. Plasma catecholamine levels revealed no significant changes before and after use of the drug; therefore, the mechanism of action may not have been mediated by catecholamine.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Cardiomyopathies; Cardiotonic Agents; Catecholamines; Dose-Response Relationship, Drug; Ethanolamines; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Pulmonary Wedge Pressure

TA-064 is a new cardiotonic agent which is also effective orally, according to investigations conducted in Japan. We analyzed computer-assisted alterations of pressure-volume relationships serially and of indirect myocardial oxygen consumption (MVO2) estimations on line during TA-064 influence in 16 patients with congestive cardiomyopathy: left ventricular function was moderately decreased in seven patients (group A) and drastically decreased in nine (group B). Results showed that TA-064, 8 micrograms/kg/min intravenously, exerted positive inotropic effects in both groups and induced mean maximal delta percentage changes at about 5 minutes of infusion as follows: left ventricular stroke work index +65% and +47%; dP/dtmax +61% and 59%; left ventricular efficiency +62% and 53%; MVO2 +31% and +11% (p less than 0.05). TA-064, 20 mg by mouth induced serum levels (group A = 23.8 +/- 12ng/ml and group B = 26.4 +/- 20 ng/ml) corresponding to the effects with dosages of 1 to 2 ng/kg/min intravenously (p greater than 0.05), thus implying that significant changes in left ventricular function require higher oral dosages. We conclude that TA-064 improves left ventricular function, primarily via a contractility increase, also in group B patients without toxic side effects. On-line indirect MVO2 assessment and analysis of serial pressure-volume relationships helped to provide a more complex definition of the mechanism and efficiency of the cardiotonic agent under study.

Topics: Administration, Oral; Adult; Cardiac Volume; Cardiomyopathies; Cardiotonic Agents; Ethanolamines; Heart Ventricles; Hemodynamics; Humans; Infusions, Parenteral; Male; Middle Aged; Myocardial Contraction; Myocardium; Online Systems; Oxygen Consumption; Pressure; Radiography; Stroke Volume