Effects of a nitric oxide synthase inhibitor in humans with septic shock

Petros, Andy; Lamb, G.C.; Leone, Anna; Moncada, Salvador; Bennett, D.; Vallance, Patrick

doi:10.1093/cvr/28.1.34

Cited by 493 publications

(200 citation statements)

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“…We demonstrate here, however, that infusion of L-NMMA, at doses which attenuated the fall in MABP caused by endotoxaemia in the pig, did not exacerbate the endotoxin-induced fall in platelet or polymorphonuclear cell counts. Similarly, in patients with septic shock, L-NMMA enhances the peripheral vascular resistence without exacerbating the thrombocytopenia or neutropenia associated with sepsis (Petros et al, 1994).…”

Section: Mortalitymentioning

confidence: 96%

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Klemm¹,

Thiemermann

Winklmaier³

et al. 1995

British J Pharmacology

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1 The present investigation compares the effects of intravenous infusion of the NO synthase inhibitor NG-monomethyl-L-argiine (L-NMMA) with that of an inhalation with NO gas in a porcine model of endotoxin (lipopolysaccharide, LPS) shock. In addition, the effects of the combination of these two treatments were also investigated. 2 Male pigs were anaesthetized and instrumented for the measurement of haemodynamic parameters. Blood samples were withdrawn at different time intervals for determination of blood gases, pH, and plasma levels of nitrite/nitrate and tumour necrosis factor. 3 Endotoxin infusion (15 tLg kg-' h-' for 3 h) caused a progressive fall in mean arterial blood pressure (MABP) and cardiac output (CO) and a biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistence (PVR). A continuous infusion of L-NMMA (0.1 mg kg' min-') significantly attenuated the fall in MABP, but did not affect MPAP, CO and PVR. NO-inhalation (50 p.p.m.) did not affect MABP, but significantly blunted the biphasic increase in MPAP and PVR and significantly delayed the fall in CO. The combination of L-NMMA infusion (0.1 mg kg-' min-') with NO-inhalation (50 p.p.m.) completely prevented the fall in MABP, significantly improved CO, and attenuated the biphasic increase in MPAP and PVR. 4 %Endotoxin also caused a decline in Pao2 and a rise of Paco2. Infusion of L-NMMA neither affected the fall in Pao2 nor the increase in Paco2. In contrast, inhalation with NO gas alone as well as the combined administration of L-NMMA infusion and NO-inhalation completely prevented the fall in Pao2 and significantly protected against the increase in Paco2. 5 Infusion of endotoxin for 180 min resulted in a mortality of 58%, which was not affected by L-NMMA (63%). In contrast, treatment of LPS-animals with either NO-inhalation alone or NOinhalation plus L-NMMA completely prevented mortality. 6 This investigation demonstrates that treatment with NO-inhalation, in order to prevent the dramatic increase in MPAP, PVR and the alterations in peripheral blood gases combined with systemic L-NMMA to improve systemic MABP and thus organ perfusion, may be a new therapeutic regimen in the treatment of septic shock.

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Section: Mortalitymentioning

confidence: 96%

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Klemm¹,

Thiemermann

Winklmaier³

et al. 1995

British J Pharmacology

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“…Several small and uncontrolled studies demonstrated that short-term nonselective NOS inhibition increased both BP and systemic vascular resistance and decreased cardiac output in patients with septic shock (65)(66)(67). Beneficial effects on renal function were, however, not reported.…”

Section: Inhibition Of Nitric Oxide Synthasementioning

confidence: 99%

Prevention and Treatment of Acute Renal Failure in Sepsis

Vriese

2003

Journal of the American Society of Nephrology

111

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“…Similarly, in vivo studies have shown that the diminished pressor response to vasoconstrictors in endotoxic shock is reversed by NOS inhibitors (Gray et al, 1991;Szabo et al, 1993). Moreover, L-NMMA can alleviate the severe hypotension associated with endotoxaemia, both in animal models (Kilbourn et al, 1990;Thiemermann & Vane, 1990) and in humans (Lin et al, 1994;Petros et al, 1994). Third, and most convincingly, transgenic mice possessing a null mutation for the iNOS gene do not become hypotensive, nor do they succumb as readily as wild-type animals to treatment with bacterial endotoxin (MacMicking et al, 1995;Wei et al, 1995).…”

Section: Introductionmentioning

confidence: 98%

Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide‐mediated diseases

Fricker¹,

Slade

Powell

et al. 1997

British J Pharmacology

129

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1 Ruthenium(III) reacts with nitric oxide (NO) to form stable ruthenium(II) mononitrosyls. Several Ru(III) complexes were synthesized and a study made of their ability to bind NO, in vitro and also in several biological systems following expression of the inducible isoform of nitric oxide synthase (iNOS). Here we report on the properties of two, related polyaminocarboxylate-ruthenium complexes: potassium chloro[hydrogen(ethylenedinitrilo)tetraacetato]ruthenate (=JM1226; CAS no.14741-19-6) and aqua [hydrogen(ethylenedinitrilo)tetraacetato]ruthenium (=JM6245; CAS no.15282-93-6). 2 Binding of authentic NO by aqueous solutions of JM1226 yielded a product with an infrared (IR) spectrum characteristic of an Ru(II)-NO adduct. A compound with a similar IR spectrum was obtained after reacting JM1226 with S-nitroso-N-acetylpenicillamine (SNAP).3 The e ect of JM1226 or JM6245 on nitrite (NO 2 7 ) accumulation in cultures of macrophages (RAW 264 line) 18 h after stimulating cells with lipolysaccharide (LPS) and interferon-g (IFNg) was studied. Activation of RAW264 cells increased NO 2 7 levels in the growth medium from (mean+1 s.e.mean) 4.9+0.5 mM to 20.9+0.4 mM. This was blocked by actinomycin D (10 mM) or cycloheximide (5 mM). The addition of JM1226 or JM6245 (both 100 mM) to activated RAW264 cells reduced NO 2 7 levels to 7.6+0.2 mM and 8.8+0.6 mM, respectively. N G -methyl-L-arginine (L-NMMA; 250 mM) similarly reduced NO 2 7 levels, to 6.1+0.2 mM.4 The e ect of JM1226 or JM6245 on NO-mediated tumour cell killing by LPS+IFNg-activated macrophages (RAW 264) was studied in a co-culture system, using a non-adherent murine mastocytoma (P815) line as the`target' cell. Addition of JM1226 or JM6245 (both 100 mM) to the culture medium a orded some protection from macrophage-mediated cell killing: target cell viability increased from 54.5+3.3% to 93.2+7.1% and 80.0+4.6%, respectively (n=6). 5 Vasodilator responses of isolated, perfused, pre-contracted rat tail arteries elicited by bolus injections (10 ml) of SNAP were attenuated by the addition of JM1226 or JM6245 (10 74 M) to the perfusate: the ED 50 increased from 6.0 mM (Krebs only) to 1.8 mM (Krebs+JM6245) and from 7 mM (Krebs only) to 132 mM (Krebs+JM1226). Oxyhaemoglobin (5 mM) increased the ED 50 value for SNAP from 8 mM to 200 mM. 6 Male Wistar rats were injected with bacterial LPS (4 mg kg 71 ; i.p.) to induce endotoxaemia. JM1226 and JM6245 (both 100 mM) fully reversed the hyporesponsiveness to phenylephrine of tail arteries isolated from animals previously (24 h earlier) injected with LPS. Blood pressure recordings were made in conscious LPS-treated rats using a tail cu apparatus. A single injection of JM1226 (100 mg kg 71 , i.p.) administered 20 h after LPS (4 mg kg 71 , i.p.) reversed the hypotension associated with endotoxaemia. 7 The results show that JM1226 and JM6245 are able to scavenge NO in biological systems and suggest a role for these compounds in novel therapeutic strategies aimed at alleviating NO-mediated disease states.

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Effects of a nitric oxide synthase inhibitor in humans with septic shock

Cited by 493 publications

References 0 publications

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Prevention and Treatment of Acute Renal Failure in Sepsis

Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide‐mediated diseases

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