The Comparative Effects of Small Intravenous Doses of L-nor- Epinephrine upon Arterial Pressure

The original observations by Oliver and Shafer of marked pressor effects occurring in animals after the intravenous injection of extracts of the adrenal medulla emphasized the biological importance of these substances (1). Later, Elliott concluded that epinephrine is involved in sympathetic nervous transmission of adrenergic effects and speculated upon its release at sympathetic nerve endings (2). In 1910, Barger and Dale suggested that not only epinephrine, but also other related sympathomimetic pressor amines might be released at sympathetic nerve endings and mediate various physiologic responses (3). Then, Loewi, in a series of brilliantly executed experiments, demonstrated that stimulation of sympathetic nerves containing adrenergic fibers to the frog's heart resulted in the release of adrenaline (4, 5). In 1946, von Euler found in animals a nor-epinephrine-like substance present in various tissues and organs containing adrenergic fibers (6). The recent chemical isolation by Tullar of the 1-isomer of nor-epinephrine from the racemic mixture of the drug (7) led to the demonstration by Luduena that this isomer is physiologically 27 to 60 times more active than the d-isomer (8). The subsequent detection of this substance in natural lots of epinephrine (9) and in extracts of adrenal medullary tumors (pheochromocytomas) (10, 11) stimulated a renewal of interest in its pharmacologic and hemodynamic actions, especially as they might relate to the problem of arterial hypertension. In a hemodynamic study in man Goldenberg and his co-workers found that the vasoconstrictor effects produced by intravenous l-nor-epinephrine were blocked by equal doses of intravenous epinephrine (12). They found that in normotensive subjects 1-nor-epinephrine produced a hypertension similar to "essential hypertension" with an increase in total peripheral resistance, but no change in cardiac output. Epinephrine, on the other hand, induced a hypertension with an increase in cardiac output and a decrease in total peripheral resistance. In patients with essential hypertension l-nor-epinephrine produced a significantly greater vasopressor response than in normotensive subjects, as judged by statistical analyses of the absolute rises in systolic and mean arterial pressure. Moreover, the reflex slowing of the pulse rate normally associated with rises in arterial pressure was frequently absent in hypertensive patients. Goldenberg suggested that the increased sensitivity of hypertensive patients to infusions of l-nor-epinephrine might be "due to lack of an antagonistic factor, epinephrine, in the peripheral nerve endings." Since a previous study in this laboratory of the effects of commercial epinephrine given in single small intravenous doses failed to reveal an abnormal sensitivity to this drug in hypertensive patients either before or after lumbodorsal splanchnicectomy (13), it was decided to carry out a similar investigation with l-nor-epinephrine.