Detrimental Hemodynamic Effects of Nitric Oxide Synthase Inhibition in Septic Shock

Robertson, Frank; Offner, Patrick J.; Ciceri, David; Becker, William K.; Pruitt, Basil A.

doi:10.1001/archsurg.1994.01420260045005

Cited by 112 publications

(47 citation statements)

References 36 publications

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“…In endotoxemic dogs, low doses of methylene blue have been shown to increase splanchnic blood flow (25). However, several investigators reported that nitric oxide synthase inhibitors caused a dosedependent reduction in mesenteric and renal blood flow, exarcebating organ vasoconstric-tion and ischemia and increasing mortality rate (5,6,32,38,39). We have studied the effects of the nitric oxide donor SIN-1 at lowto-moderate doses 1 h after endotoxic shock in dogs and we have observed a significant increase in cardiac index and superior mesenteric blood flow (41).…”

Section: Discussionmentioning

confidence: 99%

“…There are several lines of evidence indicating that an excessive liberation of nitric oxide is implicated in these hemodynamic alterations (3)(4)(5)(6). In vitro, the exposure to endotoxin and several cytokines induces several cells to produce nitric oxide (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…However, a blockade of such magnitude may be deleterious. The cardiac output decreased in several studies due to an excessive systemic vasoconstriction (17,22) and the worsening in hemodynamic status increased the mortality in animal studies (5,6). In addition, pulmonary vascular resistance is often increased during sepsis and a further increase in pulmonary arterial pressure by nitric oxide synthesis inhibitors could precipitate right heart failure.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Weingartner

Oliveira

Sant'Anna

et al. 1999

Braz J Med Biol Res

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To investigate the role of nitric oxide in human sepsis, ten patients with severe septic shock requiring vasoactive drug therapy and mechanical ventilation were enrolled in a prospective, open, non-randomized clinical trial to study the acute effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and metabolic variables were measured before and 20, 40, 60, and 120 min after the start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue administration caused a progressive increase in mean arterial pressure (60 [55-70] Arterial lactate concentration decreased from 5.1 ± 2.9 to 4.5 ± 2.1 mmol/ l, mean ± SD (P<0.05) after 60 min. Heart rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption did not change. Methylene blue administration was safe and no adverse effect was observed. In severe human septic shock, a short infusion of methylene blue increases systemic vascular resistance and may improve myocardial function. Although there was a reduction in blood lactate concentration, this was not explained by an improvement in tissue oxygenation, since overall oxygen availability did not change. However, there was a significant increase in pulmonary vascular tone and a deterioration in gas exchange. Further studies are needed to demonstrate if nitric oxide blockade with methylene blue can be safe for patients with septic shock and, particularly, if it has an effect on pulmonary function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Weingartner

Oliveira

Sant'Anna

et al. 1999

Braz J Med Biol Res

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“…The outcome thus far has been equivocal as adverse cardiovascular consequences have been observed, for example aggravated pulmonary hypertension (Robertson et al, 1994), together with reports of increased mortality in animal models (Minnard et al, 1994;Tracey et al, 1995). The capacity to discriminate between iNOS and constitutive isoforms of NOS (cNOS) is important in this context and the search for inhibitors with greater selectivity may ultimately prove fruitful.…”

Section: Introductionmentioning

confidence: 99%

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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“…ischaemia, microvascular thrombosis and mortality (Hutcheson et al, 1990;Harbrecht et al, 1992;Shultz & Raij, 1992;Wright et al, 1992). Moreover, the non-selective NOS inhibitor N0-nitro-L-arginine methyl ester (L-NAME) causes detrimental haemodynamic effects in pigs with septic shock (Robertson et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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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Detrimental Hemodynamic Effects of Nitric Oxide Synthase Inhibition in Septic Shock

Abstract: The potentiation of LPS-induced pulmonary hypertension following NAME infusion suggests that inhibition of nitric oxide synthase may have a limited role in the treatment of septic shock.

Cited by 112 publications

References 36 publications

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

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

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

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