The Role of Epinephrine in the Reactions Produced by the Endotoxins of Gram-negative Bacteria

The effects of endotoxin on the epinephrine reactivity of blood vessels in the rat mesoappendix have been studied. Following intravenous injection of a relatively small, sublethal dose of endotoxin, the terminal arterioles and venules exhibited greatly augmented and prolonged vasoconstrictor responses to epinephrine and norepinephrine. Hyperreactivity became evident within 30 minutes after injection of endotoxin, and persisted for as long as 6 hours. After larger doses of endotoxin, sufficient to cause illness or death, the vascular hyperreactivity to epinephrine was of briefer duration, and was followed by a stage of increasing hyporeactivity reaching levels much below normal. With lethal doses, the terminal arterioles and venules became completely refractory to epinephrine, while heightened reactivity persisted in the larger arteries and veins. The end result was pooling of stagnant blood in distended capillaries and venules, accompanied by the appearance of petechiae. Topical applications of epinephrine during this stage were followed promptly by an increase in petechial hemorrhage at the site of testing. Rats which were rendered tolerant to the lethal effect of endotoxin, by repeated daily injections of small doses, developed resistance to the effects of endotoxin on epinephrine reactivity. Neither hyperreactivity nor hyporeactivity to epinephrine were demonstrable in these animals, nor were spontaneous abnormalities of blood flow or petechial hemorrhages observed in the mesoappendix. Analogous results were obtained in perfusion studies of the vessels of the isolated rabbit ear. Perfusion of small amounts of endotoxin was followed within a few minutes by potentiation of epinephrine reactivity. Larger doses caused complete reversal of this effect, to such an extent that epinephrine now produced marked degrees of vasodilation. The possible meaning of these observations in the interpretation of the endotoxin-epinephrine skin lesions described in the preceding paper is discussed. It is suggested that abnormal reactions to epinephrine or norepinephrine in the tissues of intact animals may represent a basic mechanism in the intoxicating and tissue-damaging properties of endotoxin.