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The sympathomimetic action of mephentermine, like that of tyramine, is considerably reduced by procedures that deplete noradrenaline stores, such as administration of reserpine. We have, however, observed important differences between these two sympathomimetic amines in the speed with which tachyphylaxis to the pressor action develops, in their behaviour in dogs treated with reserpine before and after infusions of noradrenaline and in their action on the heart-lung preparation. Blaschko (1962) and Day & Rand (1963) concluded that the differences in behaviour, with regard to tachyphylaxis, between tyramine and a-methylated sympathomimetic amines could be explained by the resistance of the latter to attack by monoamine oxidase. The experiments reported in this paper suggest a more complex situation. METHODSMongrel dogs weighing 8 to 12 kg were anaesthetized with chloralose (150 mg/kg). In the heart-lung preparations the experimental dogs were anaesthetized with pentobarbitone (30 to 40 mg/kg) and the donors with chloroform. The blood pressure was measured from a common carotid artery by a mercury manometer and both cervical vagosympathetic trunks were cut. Heart rates were measured from electrocardiograph records. The heart-lung preparations were of the conventional type (Fawaz & Simaan, 1963). Reserpine was given as intraperitoneal injections of0.5 mg/kg 48 hr and 24 hr before the experiment; such animals usually required less anaesthetic. Noradrenaline was estimated by the method described by Fawaz & Simaan (1963). Noradrenaline was used as the bitartrate, tyramine as the hydrochloride and mephentermine (Wyamine) as sulphate, and the doses quoted are expressed in terms of the bases. Injections into anaesthetized dogs were intravenous. RESULTSThe action of tyramine and mephentermine in dogs treated with reserpineIn twelve dogs not treated with reserpine, the first injection of tyramine (2 mg) caused a rise in arterial pressure of 63±6.8 mm Hg (mean and standard error). In sixteen similar dogs mephentermine (4 mg) caused a mean rise of 70±5.7 mm Hg. But the intravenous injection of either tyramine or mephentermine caused only a slight rise in arterial blood pressure in dogs treated with reserpine (Table 1). When 2 mg of noradrenaline was infused over 50 min and tyramine (2 mg) or mephentermine (4 mg) was injected 5 to 10 min after the end of the infusion (when the blood pressure had reached a steady level), the pressor action was fully restored. The pressor action of mephentermine after the infusion was even greater than in normal dogs. These results are in harmony with those of Burn & Rand (1958) on spinal cats treated with reserpine. After the infusion of noradrenaline a

In 16 dog heart-lung preparations modified to permit a more accurate measurement of coronary flow, adrenaline or noradrenaline was infused at a rate of 4 ,ug. base/min. After a 30-mmn. pause during which the increased oxygen consumption and heart rate, but not the coronary flow, returned to pre-infusion levels, the other sympathomimetic amine was infused for the same length of time. It was found that, mole per mole, noradrenaline is as effective, and probably more so, than adrenaline in raising the oxygen consumption of the heart-lung preparation. The positive chronotropic and coronary dilating action of both amines appear to be equal. It was observed that in any one experiment the second dose of the sympathomimetic amine was slightly more effective than the first dose in raising the oxygen consumption. The main actions of adrenaline on the heart are: positive inotropic and chronotropic effects, increased atrio-ventricular conduction, and increased excitability. 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. It is also conceivable that a certain dose of adrenaline would evoke one effect and not the other. The mechanism of the coronary dilating action of adrenaline is not completely understood and it is not clear to what extent the vasodilatation is due to the rise in cardiac metabolism.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. 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) adrenaline is contraindicated in the treatment of cardiogenic shock as it increases myocardial oxygen consumption and produces symptoms of coronary

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...

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