The Mechanism of Dinitrophenol Heart Failure

Abstract

Hypoxaemia, resulting from increased tissue metabolism, is an important factor in dinitrophenol failure in the conventional heart-lung preparation. Improved oxygenation of the blood by a technique described in this paper prolongs the life of dinitrophenol-treated hearts. Dinitrophenol acts very rapidly; oxygen consumption and coronary flow increase in a few minutes and the increase is proportional to the dose. The increase in oxygen consumption diminishes with time. Dinitrophenol decreases the phosphocreatine content of the heart, even when there is no failure or hypoxia. There is no evidence that dinitrophenol failure can be due to a decrease of phosphocreatine or adenosine triphosphate content of the heart, although this is to be expected in view of the observed " uncoupling " action of dinitrophenol.Results reported by Fawaz, Hawa, and Tutunji (1957) do not answer the following questions: (a) Are the low phosphocreatine values associated with dinitrophenol heart failure due to the direct " uncoupling" action of dinitrophenol or are they caused by hypoxaemia resulting from increased metabolism ? (b) Is the decrease in phosphocreatine the cause of the failure ? Furthermore, serious objections were raised by us against the measurement of coronary sinus flow by means of the Morawitz cannula technique. The importance of measuring coronary flow accurately cannot be over-emphasized, because a decrease in systemic output may simulate failure, when in reality a corresponding increase in coronary flow may be taking place. METHODSCoronary flow was measured by the Rodbard technique (1953) as adapted to the heart-lung preparation (Badeer, 1955). We used this standard procedure in one set of experiments, ventilating the lungs with pure oxygen and bubbling oxygen through the venous reservoir. In another set of experiments the oxygenation of the blood was improved by diverting the coronary venous blood to the venous reservoir for oxygenation. This modification is illustrated in Fig. 1. The heart-lung preparation was allowed to run for a short time with the venous inflow cannula inserted into the distal end of the left pulmonary artery. The venous inflow tube was then clamped and the peripheral resistance reduced. The proximal end of the right pulmonary artery was cannulated and the coronary venous blood, collected in a beaker, was returned to the venous reservoir. The distal end of the right pulmonary artery was connected to the venous reservoir. The venous inflow was then reestablished and the peripheral resistance adjusted so that the blood pressure was maintained at 10 cm. Hg. The venous inflow level was kept at 30 to 35 cm. above the left auricle and this yielded a systemic output of 600 to 900 ml./ min., an amount similar to that obtained with the conventional heart-lung prepara- FIG. 1.-Modified heart-lung preparation to permit measurement of total coronary flow and myocardial oxygen consumption, and to improve arterial oxygen saturation in dinitrophenol experiments.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…In addition to the positive metabolic effects associated with mitochondrial uncouplers in the presence of nutrient excess, significant negative adverse effects have been associated with uncoupling agents, including DNP (74,75). The present report is an important message from not only a therapeutic perspective but also from a potential adverse effects perspective, and future work examining salicylate-based compounds should consider the fact that salicylate uncouples mitochondria at clinically relevant concentrations.…”

Ouabain‐induced Ventricular Tachycardia and Its Effect on the Performance and Metabolism of the Dog Heart

“…This is understandable when we examine the oxygen content of coronary venous blood (Table 1). We have previously shown that myocardial phosphocreatine is particularly sensitive to even short periods of hypoxia produced by ischaemia or hypoxaemia (Fawaz et al, 1957): in fact, we consider that a normal level of phosphocreatine indicates that the tissue has been properly handled before fixation. Wollenberger (1951) reported a decrease in the phosphocreatine content of the isolated dog heart during ventricular tachycardia induced by digitalis.…”

“…In view of the increased oxygen consumption observed after toxic doses, we suspect that an element of hypoxia was responsible for the low values for phosphocreatine found by Wollenberger (1951). Further, we had previously shown that the " resting" phosphocreatine values reported by Wollenberger (1951) for the isolated heart and particularly for the intact heart were too low (Fawaz and Hawa, 1953). The low phosphocreatine values reported by the same author for hearts at the onset of ventricular fibrillation induced by digitalis are obviously due to hypoxia (Fawaz et al, 1957).…”

A Study on the Mechanism of the Heart Failure Induced by Pentobarbital, Quinine, Fluoroacetate and Dinitrophenol in Dog’s Heart-Lung Preparation and Effects of Sympathomimetic Amines and Ouabain on It

“…The present result suggests, however, that it depends on presence or absence of glucose in the blood rather than on the degree of failure. Recently, Fawaz (20) examined whether the metabolic changes were actually the exact cause of DNP-induced failure, but his conclusion was negative. Rothlin (4) pointed out the fall of RQ value duri::g DNP-induc°d failure in the dog's heart-lung preparation.…”