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

Klemm, Peter; Thiemermann, C.; Winklmaier, Gisela; Pa, Martorana; Henning, Rainer

doi:10.1016/0300-9572(95)99852-2

Cited by 12 publications

(26 citation statements)

References 9 publications

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“…Additionally, minor hepatic injury was also observed in both Endo and Ctrl groups. The alteration of hepatic tests after surgery in anesthetized pigs infused with saline has already been described (21) injection of endotoxin, a minimal increase of arterial NOx (Ͻ12 µM) was measured (11,18,38) and this increase was much lower than the increase measured in rodents (20). In healthy humans, plasma NOx concentrations were between 20 and 30 µM and reached up to 150 µM during septic shock (23,28).…”

Section: Discussionmentioning

confidence: 84%

Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs

Pastor¹,

Hadengue²,

Nüssler³

2000

American Journal of Physiology-Gastrointestinal and Liver Physi

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Pastor, Catherine M., Antoine Hadengue, and Andreas K. Nussler. Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs. Am. J. Physiol. Gastrointest. Liver Physiol. 278: G416-G424, 2000.-To study the modifications of hepatic blood flow and hepatic function over time during endotoxemia, 10 pigs received a continuous intravenous infusion of endotoxin (Endo, 160 ng · kg Ϫ1 ·h Ϫ1 ) over 18 h and 7 control (Ctrl) animals received a saline infusion. The involvement of nitric oxide (NO) in this endotoxic model was assessed by measuring plasma concentrations of NO 2 Ϫ , NO 3 Ϫ , and cGMP, by testing vascular reactivity to ACh, and by evaluating inducible NO synthase (NOS 2) expression in hepatic biopsies. Endotoxin induced hypotensive and normokinetic shock in association with few modifications of hepatic blood flow, and hepatic injury was observed in both groups. Endotoxin did not increase plasma concentrations of NO 2 Ϫ , NO 3 Ϫ , and cGMP. The ACh-dependent decrease of mean arterial pressure was reduced in Endo pigs, whereas a minor difference was observed between Ctrl and Endo pigs for ACh-dependent modification of hepatic perfusion. Hepatic NOS 2 mRNA was not detected in Ctrl pigs. In Endo pigs, NOS 2 protein expression was detected only in tissues surrounding the portal vein and the inferior vena cava, whereas NOS 2 mRNA was expressed in all hepatic biopsies. Thus, although endotoxemia induces NOS 2 expression in the liver, our findings show that NO involvement is lower in pigs than in rodents during endotoxemia. liver; vascular reactivity; acetylcholine; inducible nitric oxide synthase; hepatic circulation SEPTIC SHOCK, which remains an important cause of death in intensive care units, is characterized by hypotension, vascular hyporeactivity to vasoactive agents, myocardial dysfunction, and altered regional blood flows (4, 25). The multiple-organ dysfunction syndrome, which is defined as two or more organs failing at the same time, frequently occurs and is associated with a high mortality rate. Endotoxin, which is included in the wall of Gram-negative bacteria, is responsible for most of the abnormalities observed in sepsis and is commonly used to mimic septic shock in experimental models.The liver is crucial in severe sepsis because it contains most of the macrophages of the body (Kupffer cells) able to clear endotoxin and bacteria that may stimulate the systemic inflammatory response. Moreover, hepatocytes synthesize the acute-phase proteins and enzymes necessary to modulate the inflammatory response. Finally, because hepatic blood flow represents 25% of cardiac output (CO), modifications of hepatic perfusion may greatly interfere with systemic hemodynamics.Nitric oxide (NO) is one of the major mediators that induce cardiovascular abnormalities during septic shock. Under physiological conditions, the constitutive endothelial isoform of NO synthase (eNOS or NOS 3) produces low levels of NO and regulates vascular tone as well as numerous cell functions (24). In contrast, during sepsis,...

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Section: Discussionmentioning

confidence: 84%

Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs

Pastor¹,

Hadengue²,

Nüssler³

2000

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Again, the issue will probably be highly dependent on the animal model being studied. Pigs are relatively sensitive to endotoxin and NO inhalation seems to be a very effective adjunct to sepsis treatment in these animals [215,216] whereas in rabbits some investigators observed a positive effect of gaseous NO [217] and others did not [218]. Prolonged NO inhalation therapy may result in dependence on exogenous NO due to the so-called rebound phenomenon discussed by Kiff et al [219].…”

Section: Hypotheses For Explanation Of Double-faced Role Of Nitric Oxmentioning

confidence: 99%

Involvement and dual effects of nitric oxide in septic shock

Wołkow¹

1998

Inflamm. res.

107

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Bacterial endotoxin (LPS) releases many mediators such as interleukins, tumour necrosis factor, oxygen free radicals, toxic eicosanoids, platelet activating factor, and nitric oxide (NO). LPS is a potent inducer of inducible nitric oxide synthase (iNOS). Large amounts of NO (made by iNOS) and peroxynitrite, among other factors, are responsible for the late phase of hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis and multiorgan failure in endotoxic shock. Indeed, experimental and clinical use of NOS inhibitors, which do not differentiate clearly between constitutive endothelial NOS (ceNOS) and iNOS, prevents LPS-induced hypotension. However, many detrimental effects of such NOS inhibitors are also reported, including increases in pulmonary resistance, decreases in cardiac output and organ perfusion, and even an increase in mortality of experimental animals. We believe that, in lungs, NO made by ceNOS plays a protective role against the pneumotoxic effects of LPS-released lipids such as thromboxane, leukotrienes and PAF. This is why selective iNOS inhibitors like aminoguanidine or thiourea derivatives might be preferred over nonselective NOS inhibitors for the treatment of septic shock. However, since iNOS-derived NO seems to have more than just a destructive action, the selective iNOS inhibition may be not as beneficial as expected. Accordingly, inhalation of NO gas or NO-donors in septic shock might be a complementary treatment to the use of NOS inhibitors.

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“…SIN-l is the prototype compoi however, SIN-1 has also been shown to rel radicals so that it may not be an ideal NO done has been rectified in the synthesis of some rec including pirsidomine and, more specifically 4 & Lefer, 1994 (Lefer & Lefer, 1994 (Klemm et al, 1995).…”

Section: Contractile Response To Phenylephrinementioning

confidence: 99%

Effects of S‐ethylisothiourea, a potent inhibitor of nitric oxide synthase, alone or in combination with a nitric oxide donor in splanchnic artery occlusion shock

Squadrito¹,

Altavilla²,

Squadrito

et al. 1996

British J Pharmacology

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1 The aim of this study was to compare the effects of an intravenous infusion of a potent and non selective nitric oxide synthase inhibitor S-ethylisothiourea (Ethyl-TU) with that of a nitric oxide (NO) donor on the pathological sequelae associated with splanchnic artery occlusion (SAO) shock. In addition the effects of the combination of these two treatments were also investigated. 2 SAO shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to evaluate neutrophil accumulation) and the responsiveness of aortic rings to acetylcholine (ACh, 1O nM-1O M) and to phenylephrine (PE, 1 nM-10 Mm) were studied. 3 SAO shocked rats had a decreased survival rate (0% survival 2 h after the release of occlusion) and survival time (76+10 min), increased MPO activity in the ileum (3.39+0.8 ux I-O g-' tissue), a marked leukopenia and a profound hypotension. In addition aortic rings from shocked rats showed a marked hyporeactivity to PE and reduced responsiveness to ACh. Endothelium denuded aortic rings had also a marked hyporeactivity to PE. 4 In vivo administration of Ethyl-TU (0.1 mg kg-' h-', beginning 1 min after the onset of reperfusion) significantly increased survival time and rate, improved mean arterial blood pressure, restored the responsiveness to PE, but did not change MPO activity, leukopenia or the impairment in the responsiveness of aortic rings to ACh. Addition of Ethyl-TU (2 ,UM) to endothelium denuded aortic rings in vitro, restored the marked hyporeactivity to PE. Administration of the NO donor C87-3754 (0.75 mg kg-' h-', beginning 1 min after the onset of reperfusion) slightly increased survival time and reduced MPO activity and leukopenia, but did not change survival rate and mean arterial blood pressure. In addition C87-3754 restored the responsiveness of aortic rings to ACh to control values, but did not modify the hyporeactivity to PE. The combination of these two interventions produced a higher degree of protection than either Ethyl-TU or C87-3754 alone. In fact, co-administration of Ethyl-TU plus C87-3754 completely prevented mortality, reduced MPO activity, attenuated leukopenia and the profound hypotension and restored the impaired responsiveness of aortic rings to PE and ACh. 5 Our study suggests that treatment with a nitric oxide synthase inhibitor combined with an NO donor may be a new therapeutic approach to the treatment of splanchnic artery occlusion shock.

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

Cited by 12 publications

References 9 publications

Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs

Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs

Involvement and dual effects of nitric oxide in septic shock

Effects of S‐ethylisothiourea, a potent inhibitor of nitric oxide synthase, alone or in combination with a nitric oxide donor in splanchnic artery occlusion shock

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