The Effect of Digoxin on the Intermediary Metabolism of the Heart as Measured by Glucose-C ¹⁴ Utilization in the Intact Dog

Abstract

Adniinistrntion of a therapeutic close level of digoxin in the intact clog resulted in an augmentation of the glucose utilization of the myocardium accompanied by a. greatly increased rate of glycolytic and oxidative activity. The contribution of glucose to the total metabolism of the heart was increased, and the utilization of noncarbohydrate substrates was decreased. These metabolic changes occurred in the absence of changes in the dynamic functions of the heart, indicating that the metabolic alterations were due to a primary effect of the drug rather than an effect secondary to an altered state of cardiac activity.A /ITIOUGH great advances have been made in the basic biochemical and physiological mechanisms of cardiac contractility 1 there still remains a general lack of agreement concerning the mechanism of action of the cardiac glycosides. A further knowledge of the mechanism of action of digitalis in returning the failing heart to a state of compensation would facilitate an understanding of the metabolism of the normal myocardium and the pathogenesis of cardiac failure.Studies of the changes in the substrate utilization of the heart in congestive failure 2 and after treatment with a cardiac glycoside 3 have indicated a lack of significant alteration in the metabolic activity of the myocardium. There have been no direct studies of the intermediary metabolism of the heart to substantiate these findings. Based on the utilization of C" labeled substrates by clog ventricle strips, Wollenberger 4 suggested an action of ouabaiu on metabolic processes.The following experiments were specifically designed to correlate the cardiac hemodynamic action of digoxin with possible alterations in the dynamics of the intermediary metabolic pathways involved in the myocardial utilization of glucose-C 14 in the normal dog. Methods Cardiovascular Effects of DigoxinThe cardiovascular effects of 0.065 mg./Kg\ digoxin, administered rapidly as a, single intravenous dose, wore determined in young male dogs weighing-10 to 16 Kg. The animals were anesthetized by the intravenous administration of pentobarbital sodium (25 to 35 nig./Kg.) to the point of loss of the lid reflex but presence of a cornea 1 reflex. The trachea was cannulated and the animal was allowed to breathe room air which was supplemented with oxygen via a tracheal catheter in order to insure an arterial blood oxygen content of not less than 19 volumes per cent. The carotid artery was cannulated, and a polyethylene catheter was placed in the aorta for measurement of blood pressure by means of a, Statham transducer. Venous pressure was similarly measured by means of a catheter inserted via the jugular vein and positioned at the bifurcation of the inferior and superior vena, cavae. Left ventricular pressure was obtained via a fine polyethylene catheter inserted into the left ventricular chamber by way of the carotid artery and aorta. Cardiac output, coronary blood flow (in the circumflex branch of the left coronary artery), cardiac work, cardiac arterio-venous oxygen differ...

Effect of Ouabain on the Energy Output of Rabbit Cardiac Muscle

“…• The inotropic actions of the cardiac glycosides are well established but there is still considerable controversy over their metabolic actions (1)(2)(3)(4)(5)(6). The myothermic technique has therefore been used to investigate the effects of a cardiac glycoside on cardiac energy production.…”

The Effects of α-Acetyldigoxin on Cardiac Dynamics and Myocardial Glucose and Free Fatty Acid Extraction in Nonfailing Dogs

“…The lower dose (0.05 mg/kg i.v.) corresponds to the dosage used for the evaluation of cardiovas cular effects of different types of cardiac glycosides in non-failing dogs [8,17,23,25,18,19,28]. The higher dose (0.1 mg/kg i.v.)…”

“…It is there fore hard to decide which of the biochemical changes observed under a-AD treatment are the primary ones. An increase in glu cose utilisation [19] and in cardiac galactose uptake [18] were reported after digoxin treatment in normal dogs and discussed as primary effects. However, in these experiments no simultaneous investigations of FFA metabolism were carried out.…”

Effect of Ouabain on Insulin Secretion in Man

“…However, both groups used doses four times greater than that used in the present studies, the maximum safe dose in man, whereas Milner & Hales (1967) used concentrations of ouabain 400 times greater. The observation that digoxin directly augments glucose metabolism in the intact dog heart (Kein & Sherrod, 1960) and that ouabain stimulates the uptake of glucose by isolated fat-cells (Ho & Jeanrenaud, 1967) must also be treated with reserve; in both studies the dose of glycoside used was greatly in excess of that used in clinical treatment.…”