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

Abstract

The mechanisms by which endotoxin induces a profound shock state have not been clearly established. 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. Experiments were designed to utilize some of the approaches mentioned above. MethodsStudies of endotoxin shock were performed in 71 dogs of both sexes weighing 10 to 20 kg each. All animals were anesthetized with pentobarbital sodium (30 mg per kg). These experiments may be divided into three types: a) those in which endotoxemia was induced in animals pretreated to deplete tissue supplies of histamine, catecholamines, or serotonin; b) studies in which the hemo-* Submitted for publication October 21, 1963; accepted January 23, 1964. Presented in part at the Midwestern Section Meeting of the American Federation for Clinical Research, Chicago, Ill., October 31, 1963. dynamic and chemical effects of infused histamine, catecholamines, acetylcholine, or serotonin were compared with the effects of endotoxin injection; and c) experiments in which vascular sensitivity to histamine, catecholamines, or serotonin was determined at various times before and after injecting endotoxin. The design of these experiments is outlined in Table I.Mean pressures in millimeters of Hc were monitored in arteries, veins, or perfusion circuits by pressure transducers and recorded on an oscillograph.1 Plasma concentrations of epinephrine and norepinephrine (micrograms per liter) were determined by the method of Weil-Malherbe and Bone (19) as modified in this laboratory (20). Platelet-free plasma concentrations of serotonin were determined by the method of Waalkes (21) using an interim wash with salt-saturated NaOH to remove residual traces of histidine. After the final acid extraction one sample was employed for the assay of serotonin; another sample was used for the fluorometric determination of histamine (22) Experiments and Results a) Control experimentsHeparin sodium (10 mg per kg) was administered to all dogs used for control (groups C and PV) and depletion (groups F and R) ex...

Correlation of plasma catecholamine levels with hemodynamic changes in canine endotoxin shock.

“…These findings confirm and extend the observations of others (22,24,25). The factors that sustain the hemodynamic and metabolic alterations in endotoxin shock remain largely undefined.…”

“…Neither the magnitude nor the duration of the epinephrine concentrations approached that necessary for epinephrine intoxication (17,18). Whereas some investigators (19,20) have reported that endotoxin accentuates the vascular action of small amounts of epinephrine, this additive effect has not been observed in endotoxemic dogs (21)(22)(23).…”

Simple and Combined Adrenergic Receptor Blockade in Canine Endotoxinemia

“…There appears to be little support for the hypothesis [26] that vaso dilator agents are necessary in the treatment of acute canine endotoxine mia and our observations are consistent with the assumption that the beneficial effect of isoproterenol is related to actions other than systemic vasodilatation [25], Similar to the experiments reported by Spink et al [24], the level of circulating catecholamines was not excessively high in our animals and was considerably lower than in bled dogs [10]. This, and the observation that reserpine premedication fails to improve toler ance to endotoxinemia [15] support the assumption that the toxic effect of endotoxin is not caused primarily by the action of increased catecho lamine release [24],…”

Early Histamine Release and Death Due to Endotoxin

“…Of particular concern has been a definition of the exact mechanims by which this form of shock is set into motion (3,9,11). Early cardiovascular changes have been noted which appear to follow the release of neurohumeral agents into the blood stream (1, 2, 5 , 9 ) .…”

“…Early cardiovascular changes have been noted which appear to follow the release of neurohumeral agents into the blood stream (1, 2, 5 , 9 ) . Vasoactive materials such as histamine, serotonin, bradykinin, and the catecholamines have all been implicated as being involved in the earlier phases of endotoxin shock ( 2 , 3,5,9). Reports are conflicting, however, and no clear-cut delineation has been made as to which of these substances, if any, is involved in endotoxin shock.…”