Tachyphylaxis to Epinephrine and Its Modification by Cocaine. ∗

Abstract

Summary and conclusions

1) It has been demonstrated that tachyphylaxis to epinephrine, in contradiction to earlier reports, can be made to occur both in cats and dogs; that repeated injections of large doses are required; that at a constant rate of administration, the logarithm of the tachyphylactic cumulative dose is inversely related to the size of the fixed dose per injection; that tachyphylaxis occurs only at the expense of the pressor response to the drug and not to changes in basal blood pressure level; that the tachyphylactic animal, whether cocainized or not, is protected against otherwise single lethal doses of epinephrine; and that tachyphylaxis is a reversible phenomenon. 2) It was found that cocaine very significantly accelerates the development of tachyphylaxis to epinephrine. This finding is interpreted as furnishing evidence for the existence of an important homeostatic mechanism which, by reducing the concentration of active circulating catecholamines moderates their physiological effect. This limiting mechanism has been attributed either to the capacity of tissues innervated by sympathetic nerve endings to store catecholamines or to removal of these amines by the adrenergic nerve terminals themselves. It is suggested that cocaine acts by blocking this homeostatic mechanism. As a consequence a greater concentration of circulating catecholamines occurs in the cocainized animal, its adrenergic receptors are exposed to a larger number of molecules of these amines, allowing the receptors to trigger a more vigorous response (potentiation) and to become saturated earlier (accelerated tachyphylaxis).