Treatment With Aminoethylisothiourea a Selective Inhibitor of the Inducible Isoform of Nitric Oxide Synthase Improves Liver Circulation and Oxygen Metabolism in Endotoxemia.

Sœtre, T.; Gundersen, Yngvar; Thiemermann, C.; Lilleaasen, Per; Smiseth, Otto A.; Aasen, Ansgar O.

doi:10.1097/00024382-199604001-00004

Cited by 3 publications

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“…Recently, NO has been shown to be involved in hepatic oxygen transport and consumption during endotoxemia. 16,27 Our data demonstrate that these negative effects of LPS on hepatic oxygenation can be prevented by DuP753 treatment. Following LPS challenge, burned animals in the treatment group showed a significant improvement in their mesenteric oxygenation status, as compared with nontreated animals.…”

Section: Commentmentioning

confidence: 57%

“…Nitric oxide (NO) has recently been implicated in the pathophysiology of liver injury during ischemia/reperfusion and endotoxemia. [13][14][15][16] In vitro study demonstrated that angiotensin II can decrease LPS-stimulated NO production, which is considered an endogenous nitrovasodilator, 17 by inhibiting induction of inducible form of NO synthase expression. 18 In another in vitro study, the effect of LPS on the angiotensin II receptor was found to be dose, time, and protein synthesis dependent and associated with an increased expression of the receptor gene 6.…”

Section: Commentmentioning

confidence: 99%

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Trauma- and Sepsis-Induced Hepatic Ischemia and Reperfusion Injury

2000

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Section: Commentmentioning

confidence: 57%

Section: Commentmentioning

confidence: 99%

Trauma- and Sepsis-Induced Hepatic Ischemia and Reperfusion Injury

2000

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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 Intrahepatic Endothelial Dysfunctionmentioning

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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“…In pigs with endotoxemia, injection of aminoethyl-ITU (10 mg/kg i.v. administered 3 hr after endotoxin) restores hepatic arterial blood flow to normal levels and increases hepatic oxygen consumption, without affecting cardiac output (Saetre et al, 1998). Having emphasized that some of the beneficial effects of aminoguanidine in shock may be related to its ability to inhibit iNOS activity, it should be noted that S-substituted ITUs are also likely to have effects that are unrelated to inhibition of NOS activity.…”

Section: Aminoethyl-isothiourea and Other S-substituted Isothioureasmentioning

confidence: 99%

Nitric Oxide in Sepsis

Wray

Thiemermann

Nitric Oxide and Infection

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Treatment With Aminoethylisothiourea a Selective Inhibitor of the Inducible Isoform of Nitric Oxide Synthase Improves Liver Circulation and Oxygen Metabolism in Endotoxemia.

Cited by 3 publications

References 0 publications

Trauma- and Sepsis-Induced Hepatic Ischemia and Reperfusion Injury

Trauma- and Sepsis-Induced Hepatic Ischemia and Reperfusion Injury

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

Nitric Oxide in Sepsis

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