Increased Microvascular Reactivity and Improved Mortality in Septic Mice Lacking Inducible Nitric Oxide Synthase

Abstract —Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (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 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 μm) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) ( P 50 200±56 nmol/L) compared with WT and iNOS-deficient shams (16±4 and 13±6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35±13 nmol/L, P