Repeated sublethal doses of
endotoxin render rats tolerant to lethal doses of
endotoxin and reduce
thromboxane (Tx) A2 synthesis.
Endotoxin-tolerant rats are also more resistant to lethal doses of
U46619, a stable TxA2 mimetic. These observations raised the possibility that tolerance may alter hemodynamic responses to TxA2 via one or more mechanisms. Mean arterial pressure (MAP) responses to i.v.
injections of the stable TxA2 mimetic
U46619 at doses ranging from 0.17 to 8.4 micrograms/kg were determined. Despite an initial lower systemic vascular resistance in tolerant rats compared to control rats (2.4 +/- 0.3 vs 3.1 +/- 0.2 mm Hg/ml/min/100 g of
body weight, respectively, p less than 0.05), the maximum pressor response to
U46619 was significantly greater (p less than 0.05) at the higher doses of
U46619 in tolerant rats compared to control rats. Tolerant and control rats also exhibited qualitatively different changes in MAP in response to
U46619. Control rats manifested an initial hypotensive response (15 s) not observed in tolerant rats. In contrast, tolerant rats exhibited no depressor response, but a higher peak pressor response to
U46619 than that seen in controls. Since
prostaglandins may modulate vascular responses to
U46619, subsequent studies were conducted in
indomethacin-pretreated or essential
fatty acid (EFA) deficient rats that were depleted of
arachidonic acid substrate. Either
indomethacin or EFA deficiency significantly prevented the initial hypotensive response in control rats, suggesting that
prostaglandins may mediate this response to
U46619. In additional studies, the MAP response in tolerant and control rats to the alpha 1-adrenergic agonist
phenylephrine was determined.(ABSTRACT TRUNCATED AT 250 WORDS)