Time- and surgery-dependent effects of lipopolysaccharide on gut, cardiovascular and nitric oxide functions

Lipopolysaccharide (LPS) is considered a major effector of hypotension in septic shock, partly through increasing nitric oxide (NO) formation. LPS-activation of leukocytes that express cytokines which induce NO synthase (iNOS) has also been considered an important contributor to shock. However, LPS, cytokines, and NO are not necessarily associated with hypotensive shock. We investigated whether the timing of LPS injection after initial surgery could influence responses to LPS. E. coli LPS (17 mg/kg 0111:B4 and 026:B6 serotypes) was injected 15 or 120 min after tracheal and femoral cannulation in the anesthetized rat. LPS caused hypotension for 2 h when injected 15 min (early injection) after initial surgery. LPS decreased blood pressure for only 15 min when injected 2 h (late injection) after initial surgery. Plasma NO was increased and leukocytes were decreased after both the early and late LPS injection. Blood pressure responded the same when a second surgery (ileal cannulation and luminal perfusion) followed the early or preceded the late LPS injection. Ileal NO secretion increased and effective mucosal blood flow decreased when LPS followed gut surgery, but these did not change when gut surgery followed LPS. Plasma NO was increased and leukocytes were decreased when LPS followed gut surgery, but these did not change when gut surgery followed LPS. Ileal water absorption was not affected by LPS. These observations suggest that a desensitization to the hypotensive effect of LPS develops with time after an initial trauma. An additional gut trauma does not change the blood pressure response, but does have effects on leukocyte sequestration and NO synthesis. NO synthesis alone could not explain the effects on blood pressure.