© 2000 American Heart Association, Inc.
Integrative Physiology |
Increased Microvascular Reactivity and Improved Mortality in Septic Mice Lacking Inducible Nitric Oxide Synthase
From the Sections of Critical Care and Cardiology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Ill.
Correspondence to Steven M. Hollenberg, Section of Cardiology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612. E-mail shollenb{at}rpslmc.edu
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<0.01). Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC50 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<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 vasodilation in patients with septic shock.
Key Words: sepsis • vascular reactivity • nitric oxide • inducible nitric oxide synthase • videomicroscopy
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