Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase

Persistent vasodilation characteristic of septic shock may result from over production of nitric oxide and can lead to pressor-refractory hypotension a nd death. To evaluate the significance of cytokine-inducible nitric oxide s ynthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 an d iNOS-deficient mice were made septic by cecal ligation and puncture. Trea ted mice were given fluids and antibiotics every 6 hours. Microvascular vas oconstriction in response to topical norepinephrine was measured in cremast eric arterioles (15 to 30 mu m) by videomicroscopy. Mortality at 48 hours w as significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), o r untreated WT mice (100%) (P<0.01). Norepinephrine-induced vasoconstrictio n was decreased in WT septic mice (EC50 200+/-56 nmol/L) compared with WT a nd iNOS-deficient shams (16+/-4 and 13+/-6 nmol/L), and vasoconstriction wa s significantly improved in septic iNOS-deficient mice (35+/-13 nmoVL, P<0. 01). Microvascular catecholamine responsiveness and survival were improved in iNOS-deficient mice in a clinically relevant model of sepsis, suggesting that iNOS plays an important, but not exclusive, role in refractory vasodi lation in patients with septic shock.