Comparative Pharmacology of Arterenol, Epinephrine and Isopropylarterenol* zy By GRAHAM CHEN, RUTH PORTMAN, DAVID RUSSELL, and CHARLES R. ENSOR A com arison has been made zyxwvu of the cardiovascular, bronchodilatory, spasm0 enic, hyper fycemic, and adrenal-stimulating effects of arterenol, epinephrine, an8 iso- propyfuterenol in equivalent dose levels. Epinephrine is twice as potent as arterenol in producing vasoconstriction of the vascular bed of skeletal muscles. Epinephrine acts like arterenol to produce the vaso ressor, and Like isopropylarterenol to produce the vasodepressor effect. IsopropyLerenol is three times more effective than epinephrine in prevention of histamine-induced bronchospasm in guinea pigs, while arterenol is l/~ as effective as epinephrine. Arterenol, like epinephrine, causes con- traction of isolated guinea pig's seminalvesicle, but is less active. Isopropylarterenol is devoid of a spasmogenic action. The hyperglycemic activity of arterenol is greater than that of isopropylarterenol, but less than that of epinephrine. They are equally influential on the ascorbic acid metabolism of the adrenals. RTERENOL, epinephrine, and isopropylartere- A no1 have for some time attracted the atten- tion and interest of investigators in the field of pharmacodynamics and therapeutics, especially from the relationship of chemical constitution and pharmacological action(l12). Arterenol is pri- marily a sympathomimetic excitatory, while iso- propylaterenol is a sympathomimetic inhibitory agent. Epinephrine possesses an inhibitory ac- tion greater than arterenol but less than iso- propylarterenol. That arterenol is hresent in small amounts in the adrenal medulla and that it is probably liberated from the sympathetic nerves upon stimulation (3) have given rise to speculations as to what role arterenol may play in the synthesis of epinephrine in the adrenal gland and in the transmission of adrenergic exci- tatory nerve impulses (4). By their similar phar- macological actions to epinephrine] arterenol and isopropylarterenol have been suggested for thera- peutic uses in conditions where epinephrine is indicated. Both from the pharmacodynamic and the therapeutic standpoint, therefore] it is important to know the differences in their phar- macological activities. This led us to make a quantitative comparison of the sympathomimetic properties of arterenol, epinephrine, and isopro- pylarterenol including their cardiovascular, bron- chial dilatory, spasmogenic, hyperglycemic, and adrenal cortico-stimulating actions. Some of the experimental procedures employed are differ- ent from those hitherto given in the literature. The results are presented in this report. EXPERIMENTAL I-Epinephrine,' I-arterenol bitartrate. and dl-iso- In the propylarterenol hydrochloride were used. zyxwvu * Received October zyxwvutsrq 12, 1950, from the .ReaeFch Depart- 1I-E ineph;ine was made avaigble to us hy Mr. P. H. It contains lePs then ment of Wrke Dada and Cornpan Tendid of Parke. Davis and Co. 0.10% of arterenol. Detroit, Mich. results, the doses or concentrations are given in temsof the base. Methods and Results Vasoconstriction.4prague-Dawley rats weighing between 100 and 150 Gm. were used. Local vaso- constriction was determined by the delay in onset of convulsions of rats given intramuscularly a lethal dose of strychnine nitrate (10 mg./Kg.) together with the test compound. The time of survival was also recorded. A comparison of the vasoconstricting effects of Z-epinephrine and l-arterenol is presented graphically in Fig. 1, in which the mean time of delay in onset of convulsions or the mean increase in survival time is plotted against the concentration of epinephrine and arterenol. It is seen that in equivalent dose levels, epinephrine vasoconstriction is much greater than that of arterenol. This is in agreement with the results of others obtained from vasoconstriction in perfused rabbit ear and from the enhanced effect of intradennal procaine anesthesia in guinea pigs (5). From the linear portion of the two curves for epineph- rine and arterenol, their relative vasoconstricting effects a t equal dosages have been calculated. This is obtained by a statistical treatment of data, ten determinations for each concentration, with a fac- torial design and analysisof variance (6,7). zyx Artere- no1 was thus found to be approximately one-half as effective as epinephrine in vasoconstricting activity z -0.637 * 0.052 (S. E.) calculated from the time of delay in onset of convulsions, 0.493 * 0.068 from the increased time of survival. Isopropylartenenol is a vasodilating agent; thus it produces an increase in the rate of absorption of strychnine into the circulation when they are in- jected together intramuscularly. The mean sur- vival time of 10 rats receiving 5 mg./Kg. of strych- nine nitrate is fourteen minutes and six seconds; it is three minutes and ten seconds when the same amount of strychnine is injected with 1: 100,OOO iso- propylarterenol. Blood Pressure.-Dogs or cats under pentobarbi- tal anesthesia were used. Blood pressure was measured from the carotid zyx artery; injections were given in the femoral vein. In accord with the ob- servation of others, Larterenol produces a greater hypertension than does I-epinephrine. Cocaine, 273