A comparative and interactive analysis of the effects of tumor necrosis factor alpha (TNF) and endotoxin (ETX) on selected hemodynamic and glucoregulatory alterations was performed in conscious, unrestrained, adult male Holtzman rats. Rats with indwelling carotid artery and jugular vein cannulae were administered intravenous (i.v.) bolus injections of either (1) ETX at 1.55 or 30 mg/kg; (2) TNF at 0.1, 0.5, or 1.0 mg/kg; or (3) TNF plus ETX as a low dose co-treatment at 0.1 mg/kg plus 1.55 mg/kg, respectively. Control groups received either saline or heat-inactivated TNF. TNF induced a lethal response such that 1.0 mg/kg resulted in five out of six deaths within 6 hr. Elevated pulse rates, early hyperglycemia, late hypoglycemia, hyperlactacidemia, hypoinsulinemia, and elevated catecholamine concentrations were evident after injection of 1.0 mg/kg TNF. The pathophysiological alterations observed after 1.0 mg/kg TNF were comparable to the changes observed after the administration of a highly lethal, 30 mg/kg dose of ETX (six out of six deaths within 24 hr). Co-treatment with low doses of TNF plus ETX resulted in the rapid demise of the rats, resulting in six out of six deaths within 4 hr. The resultant shocklike state was accompanied by significant hypotension, hyperglycemia and hyperlactacidemia, similar to the changes induced by highly lethal doses of TNF or ETX alone. This study supports the involvement of TNF in the pathogenesis of gram-negative septic shock and documents the hemodynamic and glucoregulatory alterations which accompany the exacerbated shocklike state induced after co-treatment with separately, minimally lethal doses of TNF plus ETX.