Involvement of Adrenergic Factors in the Effects of Bacterial Endotoxin

Abstract

The possible involvement of adrenergic mechanisms in the effects of Escherichia coli endotoxin was investigated in several preparations. Appropriate pretreatment of rabbits with E. coli endotoxin significantly increased pressor responses to epinephrine and norepinephrine as compared to untreated controls. Exposure of isolated rabbit aorta strips to E. coli endotoxin in a medium containing whole blood or cellular constituents of blood significantly increased the response to epinephrine. Endotoxin had no effect on responses to epinephrine in ritro when plain Krebs-Ringer solution was used. Pretreatment with reserpine or phenoxybenzamine (dibenzyline) protected rabbits and mice against the acute lethal effects of E. coli endotoxin. The time period intervening between reserpine or dibenzyline administration and challenge by endotoxin precluded a direct antiendotoxic action of these agents. In addition, incubation of dibenzyline with endotoxin in vitro, under conditions which would favor reaction, did not decrease the toxicity of the latter. These results indicate that peripheral adrenergic mechanisms are intimately involved in the effects of E. coli endotoxin and support the concept that deleterious effects of endotoxin in shock probably are due to exaggeration of existing vasoconstriction in an already compromised organism.

The Role of Endotoxin during Typhoid Fever and Tularemia in Man. II. Altered Cardiovascular Responses to Catecholamines*

“…Supporting this hypothesis, our previous study (2) showed that significant tolerance is acquired to the pyrogenic activity of homologous and heterologous bacterial endotoxins after typhoid fever. In the present investigation, cardiovascular reactivity to catecholamines was selected for study because increased reactivity characteristically fol-lows the injection of endotoxin into the intact rabbit and rat (4)(5)(6)(7). Moreover, intradermal testing with catecholamines during a variety of illnesses in man supports the concept that hemorrhagic responses may accompany endotoxemia (21).…”

“…In the intact rabbit and rat, marked hyperreactivity of the cutaneous * Submitted for publication November 19, 1963 and mesenteric vascular beds develops to local application of catecholamines after an initial intravenous injection of a variety of endotoxin preparations (4)(5)(6). Similarly, the systemic arterial pressor responses to intravenous catecholamines are significantly enhanced (7). Such cardiovascular hyperreactivity is sufficiently characteristic and reproducible to serve as a bioassay system for endotoxin.…”

Vasoactive Mediators as the “Trigger Mechanism” of Endotoxin Shock*

“…Several neurohumoral agents have been implicated as mediators of endotoxin shock. These include histamine (1-4), catecholamines (5-7), and serotonin (7-9).Inferences of the role played by any of these mediators have been derived from four types of evidence: a) the hemodynamic alterations observed in endotoxemia are simulated by vascular effects of the naturally occurring substance (4, 5), b) plasma concentrations of the neurohumoral agent undergo changes in endotoxin shock (7, 10-13), c) vascular reactivity to the agent is altered in endotoxemia (5,6,14), and d) pharmacological antagonists to the substance in question prevent certain responses to endotoxin (4,(15)(16)(17).That a primary role could be assigned to any single substance in endotoxin shock is doubtful, however, because of the complexity of endotoxemia and the frequently conflicting and occasionally inconclusive nature of the evidence (18). Our investigation was prompted by the uncertainties concerning the relative importance of several proposed intermediaries in the early phase of endotoxin shock.…”

“…Several neurohumoral agents have been implicated as mediators of endotoxin shock. These include histamine (1)(2)(3)(4), catecholamines (5)(6)(7), and serotonin (7)(8)(9).…”

“…Inferences of the role played by any of these mediators have been derived from four types of evidence: a) the hemodynamic alterations observed in endotoxemia are simulated by vascular effects of the naturally occurring substance (4,5), b) plasma concentrations of the neurohumoral agent undergo changes in endotoxin shock (7,(10)(11)(12)(13), c) vascular reactivity to the agent is altered in endotoxemia (5,6,14), and d) pharmacological antagonists to the substance in question prevent certain responses to endotoxin (4, [15][16][17].…”