Cardiovascular and Metabolic Effects of Whole or Fractionated Gram-Negative Bacterial Endotoxin in the Unanesthetized Rhesus Monkey

Abstract

Rhesus monkeys were infused with endotoxin lipopolysaccharide (LPS) (10 mg/kg [LPS 10 ] or 2.5 mg/kg {LPS 28 ]) or with fractions of LPS containing 6.3% lipid (PSJ or 0.5% lipid (PS 2 ) (2.5 mg/kg). Systemic and regional hemodynamics, leukocyte counts, blood gases, pH, and plasma bradykinin concentration were measured. Monkeys receiving LPS 10 , LPS 2 5 , or PS t became hypotensive (mean blood pressure -37 ± 10 mm Hg) and had decreased peripheral vascular resistance (-10% to -24% of the base line), compensated metabolic acidosis, and elevated plasma bradykinin concentrations (14 ± 6 ng/ml) 2 hours after infusion. Vasodilation occurred in coronary, hepatic, and splanchnic vasculature; vasoconstriction occurred in the spleen. Cardiac output was diverted from muscle to viscera. Monkeys receiving PS 2 were normotensive with elevated peripheral vascular resistance (+46%) and no measurable plasma bradykinin concentration. By 6 hours, marked elevation of peripheral vascular resistance developed in monkeys given LPS 10 ( + 113%) and LPS 2S (+57%). Monkeys receiving PS X returned to base-line values, but monkeys receiving PS 2 remained unchanged. Leukopenia (-50% to -65%) was persistent only in monkeys receiving LPS or PS V Toxicity of LPS apparently depends on the lipid portions of the molecule. Vasodilation and bradykinin generation are correlated with persistent granuloeytopenia. Late toxicity may be independent of early cardiovascular events. KEY WORDS lipopolysaccharidebradykinin microspheres cardiac output polysaccharides granuloeytopenia regional blood flow• Gram-negative bacterial endotoxin, a complex lipopolysaccharide, causes species-specific effects (1). Primates, both human and subhuman, develop vasodilation, granuloeytopenia, and elevated plasma concentrations of bradykinin as the initial response to endotoxemia (2-4). Although granuloeytopenia is common, vasodilation does not occur in other species exposed to endotoxin (1), and bradykinin does not participate in the endotoxinshock syndrome in these animals (5-6).Leukocyte kinin-generating capabilities differ between primates and other species (7-9), but plasma kinin-generating systems are similar (9-10). Leukocyte interactions with endotoxin depend on lipid portions of the bacterial preparation (11-12), although endotoxin-plasma interactions require only bacterial polysaccharide antigens (12).Therefore, the interaction of leukocytes with lipid portions of endotoxin may result in the generation of vasoactive substances which mediate the cardiovascular events of endotoxemia. Bradykinin may be an important mediator in the primate (3, 13). To test this hypothesis, lipid-containing and lipid-free preparations of bacterial endotoxin were infused into unanesthetized Rhesus monkeys. The results confirmed the importance of Iipids for both the generation of bradykinin and the development of hemodynamic effects. The results also supported the hypothesis that interaction of endotoxin with leukocytes is the primary pathogenetic mechanism. 346