G. Fawaz

Enzymatic Estimation of Phosphocreatine.

Summary An enzymatic micro-method has been described which permits simultaneous determination of adenosine triphosphate and phosphocreatine in extracts corresponding to 2-5 mg of muscle. The method has been found to be essentially in agreement with the colorimetric method of Fiske and Subbarow. Phosphocreatine in tissues containing more than 2% glycogen cannot be estimated by the colorimetric method and the enzymatic procedure must be used.

Mechanism of Action of Mercurial Diuretics II.

Summary 1) A method for measuring mercurial diuresis in the rat is described. The effect of varying intravenous doses of mersalyl on hydrated rats has been studied. Maximum diuresis is obtained with a dose of 4 mg Hg/kg: and the height of diuresis is reached in 2 to 3 hours. The extent of tubular damage is proportional to the dose of the mercurial. No rats survived a dose of 12 mg Hg/kg and only 50% survived a dose of 8 mg. In the animals that survived, complete tubular regeneration took place within two weeks. 2) The results reported in this paper do not support the view that mersalyl, in therapeutic doses, has any effect on the oxidative enzymes of the Krebs cycle. Mercurial diuresis may be due to interaction of mercury with —SH groups or -SH enzymes in the kidneys. It is felt, however, that such -SH groups be sought elsewhere than among the Krebs cycle enzymes and coenzymes.

Comparison of the cardiodynamic and metabolic effects of dobutamine with those of norepinephrine and dopamine in the dog isolated heart

SummaryA comparative study of the cardiodynamic and metabolic effects of norepinephrine, dopamine and dobutamine was carried out on the isolated heart-lung preparation from dogs, modified to measure coronary outflow and myocardial oxygen consumption. Infusions of the three sympathomimetic drugs which increased myocardial contractility, as reflected by maximal rate of rise of left ventricular pressure, dpldt, by 24%, produced comparable increases in heart rate of 5 to 7% with the three drugs, comparable increases in myocardial oxygen consumption of 11% with dopamine and 19% with dobutamine and a decrease in mechanical efficiency of 13% with dobutamine. At higher doses which increased dp/dt by an average of 68%, heart rate increased by 9%, 19% and 26% following norepinephrine, dopamine and dobutamine, respectively, the increase produced by dobutamine being significantly higher than that produced by norepinephrine. Myocardial oxygen consumption increased significantly following dopamine by 39% and dobutamine by 46% but not following norepinephrine. Mechanical efficiency decreased following dobutamine by 24%. At average increases in dp/dt of 123% and 166%, there were further increases in heart rate and myocardial oxygen consumption and decreases in mechanical efficiency, the changes in each parameter being similar for all three drugs. The increase in coronary outflow was compared with the spontaneous increase which is regularly observed with time in the isolated heart-lung preparation. Only dobutamine was found to increase coronary outflow by 49%, 117% and 137% at increases in dp/dt of 71%, 118% and 173%, respectively. It may be concluded from this study that, in the isolated heart, only norepinephrine can increase dp/dt by 57% without a concomitant increase in myocardial oxygen consumption and decrease in mechanical efficiency. Only dobutamine increases coronary outflow significantly above the spontaneous increase which is expected in the isolated heart-lung preparation, probably due to a more prominent direct relaxant effect on the coronary vascular bed. There is no significant difference in the arrhythmogenic effect of the three sympathomimetic drugs.

Phosphocreatine content of mammalian cardiac muscle.

Summary 1. “Resting” values for the phosphocreatine content of the ventricles of several mammalian species are reported and an explanation is offered for some of the low values recorded in the literature. The necessary precautions are noted if maximal values are to be obtained. 2. The isolated dog heart (heart-lung preparation) does not contain more phosphocreatine or adenosine triphosphate than the intact heart provided that heart failure has not set in. If, on the other hand, failure is induced by barbiturates the level of phosphocreatine increases without a change in the labile “nucleotide” phosphorus. This constitutes further evidence that this kind of heart failure is not due to the lack of production of high-energy phosphate bonds.

The effect of endogenous catecholamines and norepinephrine administration on the performance of the isolated canine heart

SummaryThe effect of endogenous catecholamines on the ability of the isolated canine heart to handle a volume load was studied in the Starling heart-lung preparation, modified to measure coronary flow and myocardial oxygen consumption. The isolated hearts were subjected to progressively increasing volume loads, and total left ventricular output and oxygen consumption were measured. Four groups of preparations were compared; controls, preparations from reserpine-pretreated dogs (0.5 mg/kg intraperitoneally 48 hrs and again 24 hrs prior to experimentation), preparations treated with 20 mg of pronethalol and preparations infused with norepinephrine (1 Μg/min for the duration of the experiment). The results show that the isolated heart depleted of its catecholamine content, or treated with pronethalol is capable of handling the same maximal volume load as a control heart. Similarly the isolated heart subjected to an infusion of norepinephrine of 1 Μg/min does not handle a bigger maximal volume load than a control heart. One may conclude from these results that in the isolated dog heart, augmentation of myocardial function, which accompanies an increase in volume work, is neither dependent on release of endogenous catecholamines, nor is it promoted by exogenously administered catecholamines.

The effect of ouabain-induced contractility on myocardial oxygen consumption.

SummaryThe present study was undertaken to explore the relationship between various doses of ouabain, myocardial contractility as reflected by the maximal rate of rise of left ventricular pressure and oxygen consumption, in the canine, nonfailing Starling heart-lung preparation modified to measure coronary flow. Concentrations of ouabain, previously found to be within “therapeutic” limits, as tested in the failing preparation, namely those attained 20 min and 30 min from the start of an infusion of ouabain (5μg/min), increased the maximal rate of rise of left ventricular pressure by an average of 13.4% and 24.2%, respectively, with no concomitant measurable increase in myocardial oxygen consumption. Changes in left ventricular work, left ventricular circumference, left ventricular end-diastolic and left atrial pressures were neither significant nor consistent. Concentrations of ouabain which induced ventricular tachycardia increased the maximal rate of rise of left ventricular pressure and myocardial oxygen consumption by an average of 205.2% and 81.4%, respectively. It may therefore be concluded from these results, that at constant aortic pressure and left ventricular dimensions an appropriate dose of ouabain induces in the isolated nonfailing heart an increase in contractility unaccompanied by a measurable increase in myocardial oxygen consumption.

Effect of Quinidine, Procaine Amide and Mersalyl on Lethal Dose of Ouabain in Isolated Dog Heart.

Summary Results obtained with isolated dog hearts do not necessarily apply to human beings, yet certain points in this paper may be considered when a combination of drugs is contemplated. The myocardial depression produced by quinidine can be counteracted with ouabain. Quinidine, in relatively large doses, neither decreased nor increased the dose of ouabain that produced ventricular fibrillation. This finding is in harmony with the results of Weiss and Hatcher(7) obtained with intact cats. Furthermore, quinidine alone, under the present experimental conditions produced no premature ventricular beats, ventricular tachycardia or ventricular fibrillation in intact dogs or isolated hearts. Procaine amide depressed the myocardium to a much lesser extent than quinidine, but in big doses it produced ventricular ectopic rhythms. Yet even these arrhythmia-producing doses of procaine amide do not influence the lethal dose of ouabain. The same thing seems to be true of mercurials. It would thus appear that the arrhythmia-producing properties of different drugs are not necessarily additive and that the danger of producing ventricular fibrillation by the combination of such drugs is perhaps exaggerated.

The effect of theophylline alone and in combination with ouabain on the isolated dog heart.

SummaryA comparative study of the inotropic effects of theophylline and ouabain as well as a study of the interaction between the two pharmacological agents were carried out in the nonfailing Starling heart-lung preparation modified to permit metabolic studies. Single doses of theophylline ranging between 100 to 200 mg added to the venous reservoir produced consistent increases in myocardial contractile force, as gauged by the maximal rate of rise of left ventricular pressure, dp/dt, 73%; systemic output, 28%; coronary output, 277%; total cardiac output, 41%; heart rate, 27%; left ventricular work, 45% and myocardial oxygen consumption, 43%. In addition, systolic time decreased consistently by 15%. 20 min and 30 min after the onset of an ouabain infusion of 5μg per min, which was started 15 min after the addition of theophylline, there was further increase in dp/dt to 87% and 107%, respectively, with no significant change in the remaining parameters from the levels attained 15 min after the administration of theophylline. As compared to ouabain administered alone, ouabain administered at peak effect of theophylline led to an earlier occurence of ventricular arrhythmias and death. It may be concluded from this study that maximally effective doses of theophylline brought about an increase in dp/dt which is greater than that brought about by maximal “therapeutic” doses of ouabain. Secondly, ouabain administered after the peak effect of theophylline was exerted led to an additional increase in dp/dt implying that the mechanisms underlying the inotropic action of each drug are different. Thirdly, at constant aortic pressure, heart rate, left ventricular enddiastolic and left atrial pressures, ouabain in the presence of theophylline brought about an increase in myocardial contractility, as gauged by an increase in dp/dt, without a concomitant increase in myocardial oxygen consumption, thus confirming earlier results obtained with ouabain alone. Fourthly, ouabain administered at peak effect of theophylline led to an earlier occurrence of ventricular arrhythmias and death.

The cardiodynamic and metabolic effects of glucagon

SummaryThe cardiac effects of a continuous infusion of glucagon at the rate of 10 μg/min were studied in the Starling heart-lung preparation, modified to measure coronary flow and myocardial oxygen consumption. A maximal increase in myocardial contractility, as reflected by maximal rate of rise of left ventricular pressure, dp/dt, of 31% was observed at a total dose of glucagon of 50 μg and was accompanied, by an increase in heart rate and in myocardial oxygen consumption of 59% and 57%, respectively. At a total dose of glucagon of 100 μg, there was an additional and comparable increase only in heart rate and myocardial oxygen consumption of 11.2% and 6.4% respectively. Similarly, at a total dose of glucagon of 150 μg, only heart rate and myocardial oxygen consumption increased additionally by increments of 2.6% and 2.9% respectively. These effects occurred at constant aortic pressure and left ventricular volume. Further infusion of glucagon led to an additional increase only in myocardial oxygen consumption of 4.2%. When the increase in heart rate was largely prevented by prior treatment with veratramine, an increase in dp/dt, not significantly different from the maximal increase obtained with glucagon alone, was accompanied by much lower and closely comparable increases in heart rate and in myocardial oxygen consumption of 15% and 19%, respectively. Coronary flow increased more markedly when glucagon was administered alone and it paralleled the increase in myocardial oxygen consumption. It may be concluded from this study that, in the isolated dog heart preparation, glucagon increases contractility, heart rate and myocardial oxygen consumption and that the increase in myocardial oxygen consumption is related more closely to the increase in heart rate than to the increase in contractility, but a minor increment is referable to a calorigenic action. The increase in coronary flow is of a secondary nature, resulting from the increase in myocardial metabolic demands.

ON THE MECHANISM OF THE PRESSOR ACTION OF TYRAMINE.

SummaryThe infusion of small amounts of noradrenaline for short periods of time into reserpinized dogs restores the pressor action of tyramine if the latter is given during the infusion but not immediately thereafter. These findings are consistent with the hypothesis that tyramine acts on its own but requires for its action the presence of noradrenaline at the receptor sites, for under these circumstances there are no stores from which noradrenaline can be released. In the normal animal, or in a reserpinized animal after repletion of the stores by prolonged noradrenaline infusion, tyramine is envisaged to act by releasing from the stores a sufficient amount of noradrenaline which in turn “catalyses” the action of tyramine at the receptor sites. These results do not support the view that tyramine, like guanethidine, acts solely by virtue of the amount of noradrenaline it releases.