Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock

Petros, Andy; Bennett, David; Vallance, Patrick

doi:10.1016/0140-6736(91)92376-d

Cited by 835 publications

(327 citation statements)

References 7 publications

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“…Inhibitors of NO synthase restore arterial pressure and vascular resistance (Kilbourn et al, 1990) in animal models of septic shock, but worsen the prognosis if excessive doses are given (Nava et al, 1991). NO synthase inhibitors (Petros et al, 1991) and the guanylate cyclase inhibitor, methylene blue (Schneider et al, 1992) have been administered to patients with septic shock but depression of cardiac index has been observed (Petros et al, 1991;Schneider et al, 1992), prompting other authors to advise caution (Hotchkiss et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis

Herity

Allen

Silke

et al. 1994

British J Pharmacology

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1 The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of nicardipine, theophylline or the cyclic GMP-selective phosphodiesterase inhibitor, zaprinast (M&B 22948). 2 In pentobarbitone-anaesthetized pigs, haemodynamic indices were measured before and after intravenous administration of NG-nitro-L-arginine methyl ester (L-NAME) in a dose-response protocol (0.2-20 mg kg-'; n = 6) and as a single bolus of 10 mg kg-' either alone or followed by increasing doses of nicardipine, theophylline or zaprinast (n = 8 in each group). 3 L-NAME caused a dose-dependent rise in systemic vascular resistance and mean systemic arterial pressure and a dose-dependent fall in cardiac output. A single bolus of L-NAME (10 mg kg-') produced these effects within 15 min. 4 Subsequent administration of nicardipine (0.05-0.2 mg kg-') caused complete reversal of systemic vasoconstriction and hypertension and in doing so completely restored cardiac output. Theophylline (7.5-1O mg kg-') partially reversed the rise in systemic vascular resistance and partially restored cardiac output but the effect was small compared to that of nicardipine. Zaprinast (1-5 mg kg-') had no significant effect on any of these variables. 5 These results suggest that reduced cardiac output following inhibition of NO synthesis is an effect of increased afterload on the heart and is reversible by nicardipine and to a lesser extent by theophylline. These findings may have potential value for those using NO synthase inhibitors to treat patients with septic shock.

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Section: Discussionmentioning

confidence: 99%

Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis

Herity

Allen

Silke

et al. 1994

British J Pharmacology

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“…11 The use of pharmacological NOS inhibitors in patients with septic shock increases blood pressure and restores vascular resistance. 12 Furthermore, NOS2-deficient mice do not experience the impaired vasoconstriction associated with endotoxemia. 13 This excessive production of vasoactive mediators, such as NO, results in the impaired vasoconstriction and associated hypotension seen in patients with sepsis.…”

Section: Vasoregulationmentioning

confidence: 99%

Lipopolysaccharide signaling in endothelial cells

Dauphinee

Karsan

2006

Laboratory Investigation

528

433

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Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gramnegative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-jB (NF-jB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-jB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

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“…with hemorrhagic and septic shock (Petros et al, 1991) as well as direct cell cytotoxicity seen in chronic inflammatory conditions (Koprowski et al, 1993).…”

Section: Nitric Oxide Suppresses Inducible Nitric Oxide Synthase Exprmentioning

confidence: 99%

Nitric oxide suppresses inducible nitric oxide synthase expression by inhibiting post-translational modification of IκB

Chang

Lee²,

Cheong³

et al. 2004

Exp Mol Med

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Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock

Cited by 835 publications

References 7 publications

Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis

Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis

Lipopolysaccharide signaling in endothelial cells

Nitric oxide suppresses inducible nitric oxide synthase expression by inhibiting post-translational modification of IκB

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