ADRENERGIC BLOCKADE OF THE MAMMALIAN HEART BY A DICHLORO ANALOGUE OF ISOPROTERENOL

DCI, a dichloro analogue of isoproterenol (β - hydroxy - N - isopropyl - 3,4 - dichloro - phenethylamine hydrochloride; Lilly 20522), selectively blocks the cardiac positive inotropic and chronotropic effects of adrenergic stimuli in dogs with intact circulatory systems and in isolated hearts of rabbits. In dogs complete blockade of the cardiac positive inotropic effects of small doses of epinephrine, norepinephrine and isoproterenol and of supramaximal stimulation of the cardiac sympathetic nerves is obtained with cumulative doses of DCI of 3 mg/kg and greater. Depression of contractile force was frequently observed in response to sympathomimetic amines and to sympathetic nerve stimulation after administration of large doses of DCI. No inhibition of the positive inotropic effects of digoxin, theophylline or calcium chloride was observed. In dogs blockade of the positive chronotropic effects of isoproterenol but not of theophylline was obtained with DCI. In isolated rabbit hearts DCI has qualitatively the same blocking action on the effects of the amines but not on those of calcium, theophylline or ouabain. The dichloro analogues of epinephrine (DCE) and norepinephrine (DCNE) have similar blocking actions to those of DCI but are less potent. DCI, in both dog and rabbit heart, initially stimulates and with subsequent doses depresse the heart. DCNE has similar effects in the dose but in the rabbit heart it, like DCE, produces only depression. The cardiac depressant effects are not antagonized by atropine. Ephedrine, which also produces initial cardiac stimulation and subsequent depression with high doses in the dog, does not inhibit the cardiac stimulant actions of other sympathomimetic amines. The vasopressor effect of epinephrine in dogs is potentiated by DCI, that of norepinephrine is relatively unchanged, while that of cardiac sympathetic nerve stimulation is blocked, presumably due to the cardiac blockade. The vasodepressor effect of isoproterenol is completely blocked, but not reversed, by DCI in the dog. DCI, on intravenous administration, transiently lowers blood pressure, while DCNE produces a prolonged rise. DCNE does not appear to inhibit the vasopressor actions of epinephrine and norepinephrine or the vasodepressor action of isoproterenol. On the basis of the selective blockade by DCI of the excitatory effects of adrenergic stimuli on the heart and of their inhibitory effects on other organs ( e.g. , the vasodepressor effect of isoproterenol) and the lack of blockade of adrenergic vasopressor action, it is concluded that the adrenergic receptors of mammalian hearts are functionally homologous to the adrenergic inhibitory receptors of other tissues. This conclusion agrees with the hypothesis of Ahlquist that the cardiac inotropic and chronotropic sympathetic receptors are of the beta type, receptors which subserve inhibitory functions in other organs, in contrast to the alpha receptors which subserve sympathetic excitatory responses in all organs except the heart.