Aminoethyl-Isothiourea, a Selective Inhibitor of Inducible Nitric Oxide Synthase Activity, Improves Liver Circulation and Oxygen Metabolism in a Porcine Model of Endotoxemia

Sætre, T.; Gundersen, Yngvar; Thiemermann, Christoph; Lilleaasen, Per; Aasen, Ansgar O.

doi:10.1097/00024382-199802000-00006

Cited by 31 publications

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“…In our study, the mortality rate was lower because 13 pigs were infused with endotoxin and only 3 pigs died before the end of the experiment. As observed in the present study, most of the porcine models of sepsis described hypotensive and normo-or hypokinetic shock with pulmonary hypertension (30,35). This model was also characterized by hemoconcentration, decreased platelet count, leukopenia, and metabolic acidosis.…”

Section: Discussionsupporting

confidence: 75%

“…In the present study, hepatic perfusion was not significantly modified over time in both groups. Recently, in anesthetized pigs, Saetre et al (30) found a severe hepatic hypoperfusion within 3 h of endotoxin infusion that was reversed by the selective iNOS inhibitor aminoethyl-isothiourea. Concomitantly, hepatic DO 2 decreased, whereas hepatic V O 2 was maintained constant by the hepatic O 2 extraction increase (30).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, in anesthetized pigs, Saetre et al (30) found a severe hepatic hypoperfusion within 3 h of endotoxin infusion that was reversed by the selective iNOS inhibitor aminoethyl-isothiourea. Concomitantly, hepatic DO 2 decreased, whereas hepatic V O 2 was maintained constant by the hepatic O 2 extraction increase (30). Minor and transient hepatic hypoperfusion were also observed after a single bolus injection of endotoxin by Maeda et al (21).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…24 Finally, the observed ineffectiveness of preferential iNOS-inhibition on liver perfusion pressure in conditions of endotoxemia shows the predominant importance of eNOS-derived NO production for intrahepatic hemodynamics. 25,26 In liver cirrhosis vasorelaxation in response to receptor-dependent and -independent eNOS-agonists, such as acetylcholine and Calcium-Ionophore A23187, is drastically reduced. 9 Moreover, it seems that this vasodilatory impairment correlates with the severity of the cirrhotic process; this effect is more evident in cirrhotic rats with ascites whose liver exhibit rather paradoxic vasoconstriction in response to acetylcholine, an endothelial relaxing agonist (Fig.…”

Section: Mechanisms Of Action In Intrahepaticmentioning

confidence: 99%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

2002

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C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

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“…24,25 This is associated with local failure of microvascular perfusion 23 and the development of patchy necrosis. 24 At the same time, although iNOS is increased under these conditions, specific iNOS antagonists have little effect on liver perfusion 26,27 ; their effect, if any, is amelioration of injury possibly more through support of the systemic circulation than of a direct effect on the liver. 28 These data suggest that NO is necessary to maintain sinusoidal perfusion but that the relatively small amount generated by eNOS is adequate.…”

Section: Blood Flow Regulationmentioning

confidence: 99%

Nitric oxide in liver injury

1999

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Aminoethyl-Isothiourea, a Selective Inhibitor of Inducible Nitric Oxide Synthase Activity, Improves Liver Circulation and Oxygen Metabolism in a Porcine Model of Endotoxemia

Cited by 31 publications

References 0 publications

Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs

Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

Nitric oxide in liver injury

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