A Further Note on the Mechanism of Action of Endotoxin. ∗

Abstract

Death from endotoxin is the result of injury to vascular muscle, which leads to a progressive decline in venous return, and consequently to a fall in cardiac output that is incompatible with survival (1). In a previous communication evidence was given that the injury to vascular muscle by endotoxin is inflicted indirectly, i.e., by virture of its neurotoxic action, and not because of any direct action upon this muscle(2). The experimental data in support of this view are:

(a) the severity and lethality of peripheral vascular collapse produced by 2000 gamma of an endotoxin given intravenously is equalled by that following 100 gamma injected subdurally(3), and by that following one or two gamma of endotoxin placed in direct contact with the coeliac ganglion (4,5);

(b) in an animal dead from endotoxic shock the tissues of a denervated area including vascular muscle are free of the injuries that are present in a corresponding area that is not denervated. Thus, prophylactic denervation of the splanchnic viscera by coeliac blockade prevents hemorrhagic necrosis of the intestinal mucosa except in the distal half of the colon(6).

Coeliac blockade also prevents death from a lethal dose of endotoxin. This is because the elimination of vasoconstriction in this area not only preserves the integrity of the liver and spleen, but allows better access for the clearance and detoxification of circulating endotoxin by the RE system in these tissues.

The foregoing evidence for the neurotoxic hypothesis notwithstanding, one can expect considerable hesitation in accepting it because of other potentially lethal effects on the vascular system that might be the result of direct action of the endotoxin (e.g., myo-cardial necrosis, degeneration of intima, capillary rupture, changes in platelets, leukocytes, titer of circulating plasminogen and fibrino-gen) and that might also be prevented by preserving liver function.