The Effect of Dinitrophenol, Hypoxaemia and Ischaemia on the Phosphorus Compounds of the Dog Heart

Abstract

The results reported in this paper indicate that dinitrophenol acts directly on the isolated heart, increasing its metabolic rate. It also produces heart failure associated with a low phosphocreatine content of the muscle but with no change in adenosine triphosphate, which may or may not be due to a relative hypoxia of the cardiac tissue. Experimental arterial hypoxaemia, if severe, produces a similar picture of heart failure with a decrease in phosphocreatine and no change in adenosine triphosphate. Ligation of the coronary arteries results in disappearance of the major part of the phosphocreatine within a few minutes regardless of whether or not ventricular fibrillation ensues; the adenosine triphosphate remains unchanged.2: 4-Dinitrophenol increases oxidative metabolism in animals several-fold by direct cellular action (Tainter and Cutting, 1933). It is also known to uncouple phosphorylation and oxidation in tissue homogenates or particulate systems derived therefrom (Loomis and Lipmann, 1948). Hence, if dinitrophenol were added to a welloxygenated heart-lung preparation, one would expect to observe a failure of the heart. This failure would be due to lack of production of high-energy phosphate bonds, instead of lack of utilization of such bonds as is the case in heart failure due to barbiturates (Wollenberger, 1947;Fawaz and Hawa, 1953). This study was undertaken to determine to what extent observations made on homogenates and simpler systems can be applied to organs in activity. Since dinitrophenol may produce relative hypoxia by increasing metabolism, the effects of arterial hypoxaemia and ischaemia on the phosphorus compounds of the heart were also studied. METHODSPentobarbitone anaesthesia was used in all animals. Heart-lung preparations were made by the conventional procedure except that the blood donors were anaesthetized with chloroform.Detailed information for preparing samples from the left ventricle and for estimating the phosphorus compounds has been described previously (Fawaz and Hawa, 1953). In the present work, the labile nucleotide phosphorus was determined by hydrolysing the trichloracetic acid filtrate in N-HCl for 7 instead of 10 min. Experiments with pure crystalline adenosine triphosphate (ATP) showed that this was a sufficient period for 2/3 of the ATP phosphorus to be liberated. Our values are therefore slightly lower than before. In several control experiments and in a dinitrophenol experiment we compared the results obtained by this method with the paper chromatographic method for ATP determination. Nucleotides were precipitated from the trichloracetic acid filtrates with mercuric acetate (Kerr, 1940). After removal of the mercury by H2S and evaporation to a small volume, the nucleotides were chromatographed on filter paper by the method of Magasanik, Vischer, Doniger, Elson, and Chargaff (1950). It was found that at least 90% of the 7 min. value, as determined on the trichloracetic acid filtrate, was accounted for by true ATP.The phosphorus values in this paper are expressed not as...

The Mechanism of Dinitrophenol Heart Failure

“…Yet the conclusion cannot be drawn that dinitrophenol failure is due to its action of uncoupling phosphorylation and oxidation with the resulting unavailability of highenergy phosphate bonds. (Fawaz, 1956). Fluoroacetate is also a substance which blocks the Krebs cycle at the citrate stage and would be expected to produce failure due to lack of availability of high-energy phosphate bonds.…”

The Effects of Adrenaline and Noradrenaline on the Metabolism and Performance of the Isolated Dog Heart

“…Furthermore, a study has been made of the effect of graded doses of adrenaline, to see if the inotropic action can be separated from the calorigenic action. This study appeared important in view of statements often encountered in the clinical literature that (a) adrenaline raises the blood pressure mainly by virtue of its action on the heart, increasing the cardiac output, whereas noradrenaline acts peripherally; (b) (Fawaz and Tutunji, 1959 Gollwitzer-Meier and Witzleb (1952) are the only investigators who have studied the calorigenic effect of noradrenaline on the isolated denervated dog heart and they came to the opposite conclusion. They injected single doses of noradrenaline (20 to 40 jig.)…”

“…In addition to these, there is the " calorigenic " effect. This is the increase in cardiac oxygen consumption which cannot be explained solely by the rise in heart rate and increase in work performed (for literature see Gollwitzer-Meier, Kramer and Kruger, 1936).All these effects of adrenaline need not have the same mechanism of action at the cellular or subcellular (enzymatic) level. Krayer (1949), for instance, has shown that the chronotropic action but not the inotropic action can be inhibited by veratramine.…”

“…In addition to these, there is the " calorigenic " effect. This is the increase in cardiac oxygen consumption which cannot be explained solely by the rise in heart rate and increase in work performed (for literature see Gollwitzer-Meier, Kramer and Kruger, 1936).…”

“…In addition to these, there is the " calorigenic " effect. This is the increase in cardiac oxygen consumption which cannot be explained solely by the rise in heart rate and increase in work performed (for literature see Gollwitzer-Meier, Kramer and Kruger, 1936 In this study a comparison has been made between the "calorigenic," chronotropic, and coronary dilating actions of (-)-adrenaline and (-)-noradrenaline on the dog heart-lung preparation and the effect of these compounds on the phosphorus compounds of the heart. Furthermore, a study has been made of the effect of graded doses of adrenaline, to see if the inotropic action can be separated from the calorigenic action.…”