Comparison of the effects of aminoguanidine and Nω-nitro-l-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat

doi:10.1016/0014-2999(95)00877-2

European Journal of Pharmacology

Volume 300, Issues 1–2, 4 April 1996, Pages 99-104

https://doi.org/10.1016/0014-2999(95)00877-2 Get rights and content

Abstract

This study compares the effects of aminoguanidine, a relatively selective inhibitor of inducible nitric oxide (NO) synthase, and N^ω-nitro-l-arginine methyl ester (L-NAME), a selective inhibitor of endothelial NO synthase, on hypotension and multiple organ dysfunction caused by endotoxaemia in the anaesthetised rat. In the sham-operated rats, L-NAME, but not aminoguanidine, caused a dose-dependent increase in blood pressure. Endotoxin caused hypotension, increases in plasma nitrite (an indicator of inducible NO synthase activity), and dysfunction of kidney, liver and pancreas. Treatment of endotoxic rats with aminoguanidine or L-NAME caused significant and sustained rises in blood pressure. The increase in plasma nitrite caused by endotoxin was inhibited by aminoguanidine, but not by L-NAME. Aminoguanidine, but not L-NAME, attenuated the renal, liver and pancreatic dysfunction caused by endotoxaemia. Thus, selective inhibition of inducible (aminoguanidine), but not endothelial NO synthase (L-NAME) attenuates the circulatory failure and the multiple organ failure caused by endotoxaemia.

References (17)

K. Hasan et al.
Inhibition of nitric oxide formation by guanidines
Eur. J. Pharmacol.
(1993)
K.D. Kroncke et al.
Pancreatic islet cells are highly susceptible towards the cytotoxic effects of chemically generated nitroc oxide
Biochim. Biophys. Acta
(1993)
T.P. Misko et al.
Selective inhibition of the inducible nitric oxide synthase by aminoguanidine
Eur. J. Pharmacol.
(1993)
A. Petros et al.
Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock
Lancet
(1991)
C. Thiemermann
The role of the l-arginine-nitric oxide pathway in circulatory shock
Adv. Pharmacol.
(1994)
J.A. Corbett et al.
Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction
Diabetes
(1992)
M.J.D. Griffiths et al.
Aminoguanidine selectively inhibits inducible nitric oxide synthase
Br. J. Pharmacol.
(1993)
S.S. Gross et al.
Macrophage and endothelial nitric oxide synthesis: cell-type selective inhibition by N^G-aminoarginine, N^G-nitroarginine and N^G-methylarginine
Biochem. Biophys. Res. Commun.
(1991)

There are more references available in the full text version of this article.

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Additionally, ROS participates in the conduction of various inflammatory signaling molecules and is responsible for cell survival and necrosis (Kim et al., 2010; Mittal et al., 2014). The accumulation of nitric oxide (NO) in hepatocytes could recruit excessive KCs into the liver and aggravate hepatotoxicity (Wu et al., 1996; Gardner et al., 1998; Laskin and Pilaro, 1986). KCs activation was also reported to promote reactive oxygen species (ROS) and nitrogen species formation, which led to hepatocytes necrosis (Michael et al., 1999).
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The poly-γ-d-glutamic acid capsule surrogate of the Bacillus anthracis capsule induces nitric oxide production via the platelet activating factor receptor signaling pathway
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Mice deficient in inducible nitric oxide synthase (iNOS) have been shown to be resistant to LPS-induced mortality (Wei et al., 1995) and vascular hypocontractility (Gunnett et al., 1998). Moreover, inhibitors of NO production have shown beneficial effects to patients with severe sepsis as well as to animals in experimental sepsis (Wu et al., 1996; Liaudet et al., 1997; Petros et al., 1994). Exposure of immune cells to various inflammatory cytokines, bacteria, or bacterial components such as LPS, lipoteichoic acid (LTA), and peptidoglycan generates NO production from L-arginine via inducible nitric oxide synthase (iNOS) expression (Bogdan, 2001).
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This precipitates circulatory failure, which is associated with a substantial increase in mortality [21]. The inhibition of NOS activity by a selective inhibitor of iNOS activity can attenuate the hepatic, renal and pancreatic dysfunction associated with LPS-induced endotoxemia in rats [22]. In addition, overproduction of NO and NO-dependent free radicals seems to be related to the development of multiple organ failure in cases of endotoxic shock.
Dried roots of Scutellaria baicalensis Georgi (Huang qin) are widely used in traditional Chinese medicine. Baicalein is a major bioactive flavonoid component of H. qin that shows a wide range of biological activities, including antioxidant and anti-inflammatory actions. We evaluated therapeutic effects and possible mechanisms of action of baicalein on circulatory failure and vascular dysfunction during sepsis induced by lipopolysaccharide (LPS; 10 mg/kg, i.v.) in anesthetized rats. Treatment of the rats with baicalein (20 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes of hypotension and tachycardia caused by LPS and significantly inhibited the elevation of plasma tumor necrosis factor α (TNF-α). Baicalein also decreased levels of inducible nitric oxide synthase (iNOS) and the overproduction of NO and superoxide anions caused by LPS. It also increased the survival rate of ICR mice (25–30 g) challenged by LPS (60 mg/kg). Moreover, infiltration of neutrophils into the liver and lungs of rats 6 h after treatment with LPS was also reduced by baicalein. To investigate the mechanism of action of baicalein on sepsis, RAW 264.7 cells were used as a model. Baicalein inhibited iNOS protein production, and suppressed LPS-induced degradation of IκBα, the formation of a nuclear factor kappa B (NF-κB)-DNA complex and NF-κB-dependent reporter gene expression. Thus, the therapeutic effects of baicalein were associated with reductions in TNF-α and superoxide anion levels during sepsis. The inhibitory effects of baicalein on iNOS production may be mediated by inhibition of the activation of NF-κB. Baicalein may thus prove a potential agent against endotoxemia.
Sepsis: Emerging role of nitric oxide and selectins
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Sepsis—a state of systemic bacterial infection—often leads to multiorgan failure and is associated with high mortality despite the recent advances achieved in intensive care treatment. Many of the ill effects of sepsis are attributed to an abnormally enhanced host inflammatory response that leads to neutrophil recruitment and activation involving selectins, a class of adhesion molecules, in the initial stages. Nitric oxide and its various isoforms have also been implicated in various vascular alterations and directly participate in the cellular toxicity in sepsis. This review briefly describes the role of selectins and nitric oxide in experimental and clinical sepsis as well as the therapeutic outcomes of blocking therapies.
Sepse – um estado de infecção bacteriana sistêmica – frequentemente leva à falência múltipla de órgãos e associa-se a altos índices de mortalidade, apesar de progressos recentes no manejo de pacientes em unidades de terapia intensiva. Muitos dos efeitos maléficos associados à sepse são atribuídos a uma resposta inflamatória patologicamente ampliada que leva a recrutamento neutrofílico e ativação das moléculas de adesão do grupo das selectinas, durante as fases iniciais do processo. O óxido nítrico e sua diversas isoformas também foram implicados nas diversas manifestações vasculares da sepse como participantes diretos da toxicidade celular. Esta revisão descreve o papel das selectinas e do óxido nítrico em situações clínicas e experimentais de sepse, bem como os respectivos efeitos de processos terapèuticos de bloqueio.
Endotoxin releases a substance from the aorta that dilates an isolated arteriole by up-regulating INOS
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Citation Excerpt :
The use of iNOS selective inhibitors may be an alternative approach in the treatment of septic shock by preventing the deleterious effects of eNOS inhibition. Wu et al. compared the use of aminoguanidine and l-NAME in rats exposed to endotoxin and found increased survival in the aminoguanidine group [18]. The aminoguanidine group was also found to have less renal, liver, and pancreatic dysfunction than the l-NAME group [19].
Loss of vascular tone in resistance arterioles has been implicated as the cause of hypotension in septic shock. It is believed that the overproduction of nitric oxide (NO) by the inducible isoform of nitric oxide synthase (iNOS) results in the vasodilatation seen in septic shock. However, we have shown that endotoxin has no effect on vascular tone of an isolated resistance vessel unless the endotoxin flows over a segment of aorta or vena cava upstream in the superfusion line. The aim of this study was to determine if the subsequent vasodilation was due to the release of a direct vasodilator or production of NO in the arteriole and if its source was iNOS by using its selective inhibitor, aminoguanidine.
First-order rat cremaster arterioles (n = 36) were isolated and cannulated onto micropipettes, superfused with physiological buffer at 34°C, pressurized to 70 mm Hg, and allowed to gain spontaneous tone over 90 min. A segment of abdominal aorta was then placed in series with the arteriole so that the superfusate passed over the aorta and then into the tissue bath containing the isolated arteriole. The vessels were allowed to equilibrate over 60 min. During this interval, the arteriole was exposed to l-NAME (100 μm), aminoguanidine (100 μm), or buffer. The aorta and arteriole were then superfused with endotoxin (Salmonella enteritidis 2.5 μg/ml). Internal diameters of cannulated arterioles were measured and recorded with videomicroscopy and videocalipers at a resolution of ±1 μm every 15 min for 1 h. Six groups were created with n = 6 for each group: Group 1, endotoxin; Group 2, control; Group 3, l-NAME and endotoxin; Group 4, l-NAME; Group 5, aminoguanidine and endotoxin; and Group 6, aminoguanidine.
After the 60-min equilibration period, there was no significant difference in resting tone among the six groups. At t = 120, the percentage of tone in the control group was 42.7 ± 0.4% (mean ± SEM) and this was not changed by treatment with aminoguanidine (42.2 ± 0.7%). However, exposure to l-NAME alone resulted in vasoconstriction with a gain in tone to 49.5 ± 1.6% (P > 0.05). Endotoxin alone caused arteriolar tone to fall to 33.5 ± 1.2% (P < 0.05). Arterioles treated with aminoguanidine did not lose tone (42.6 ± 1.7%) when exposed to endotoxin and arterioles treated with l-NAME retained their elevated tone (46.0 ± 2.2%) after treatment with endotoxin.
This study demonstrates that the aorta exposed to endotoxin releases a substance that vasodilates resistance arterioles through the up-regulation of iNOS. Aminoguanidine prevented the fall in tone following exposure to endotoxin, while use of the nonselective NOS inhibitor, l-NAME, not only blocked the fall due to endotoxin but increased basal tone by blocking the constitutively active eNOS.
The effects of selective nitric oxide synthase blocker on survival, mesenteric blood flow and multiple organ failure induced by zymosan
2005, Journal of Surgical Research
Circulatory failure in multiple organ dysfunction syndromes (MODS) is characterized with systemic vasodilation, diminished blood flow to various vascular beds. The aim of this study was to investigate the effects of selective inhibition of nitric oxide on the mesenteric arterial blood flow (MABF), survival and organ injury of the liver, kidney, lung and spleen in zymosan-induced MODS.
Forty Swiss albino mice (20–40 g), 7 to 9 weeks old, were obtained. Animals were randomly divided into four groups. The first group were treated intraperitoneally (i.p) with vehicle (saline) and served as a sham group for aminoguanidine (AG) (n = 10). The second group was treated with zymosan (500 mg/kg, suspended in saline solution, i.p). The mice in the third and fourth group received AG (15 mg/kg) 1 h and 6 h after zymosan or saline administration, respectively. Eighteen hours after the administration of zymosan, animals were assessed for MODS described subsequently. The signals from the flowmeter were also recorded on mesenteric arterial blood flow values.
In zymosan-treated animals, the MABF was significantly lower than that of solvent (saline)-treated controls (ml min⁻¹, controls: 4.6 ± 0.6; zymosan: 1.6 ± 0.9, P < 0.05). When animals were treated with AG, there were no significant differences in MABF values between AG group and solvent (saline)-treated control group. However AG prevented zymosan-induced mesenteric MABF decrease. Treatment with aminoguanidine also decreased mortality.
AG is capable of inhibiting both the induction and the activity of the already iNOS; it remains a potential therapeutic agent in patients with MODS.

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¹: Present address: Department of Pharmacology, National Defense Medical Center, P.O. Box 90048-504, Taipei, Taiwan, R.O.C.

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Short communicationComparison of the effects of aminoguanidine and Nω-nitro-l-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat

Abstract

Eur. J. Pharmacol.

Biochim. Biophys. Acta

Eur. J. Pharmacol.

Lancet

Adv. Pharmacol.

Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction

Diabetes

Aminoguanidine selectively inhibits inducible nitric oxide synthase

Br. J. Pharmacol.

Macrophage and endothelial nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine

Biochem. Biophys. Res. Commun.

Short communication
Comparison of the effects of aminoguanidine and N^ω-nitro-l-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat

Macrophage and endothelial nitric oxide synthesis: cell-type selective inhibition by N^G-aminoarginine, N^G-nitroarginine and N^G-methylarginine