Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis

Nm, Atucha; Shah, Vijay H.; García‐Cardeña, Guillermo; Sessa, WE; Groszmann, R. J.

doi:10.1016/s0016-5085(96)70026-4

Cited by 84 publications

(83 citation statements)

References 3 publications

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“…Induction of liver cirrhosis in rats by CCl 4. Male SpragueDawley rats (Harlan Sprague Dawley Inc., Indianapolis, Indiana, USA), weighing 100-125 g, underwent inhalation exposure to CCl 4 and had phenobarbital (0.35g/L) added to their drinking water, as described previously by ourselves and others (4,5).…”

Section: Methodsmentioning

confidence: 99%

“…A classic expression of these hemodynamic abnormalities is an impairment in vascular contractility, with resulting hyporeactivity to vasoconstrictors (4)(5)(6)(7)(8)(9). This has been demonstrated to be caused largely by overproduction of endotheliumderived vasodilators, mainly nitric oxide (NO) (5-7, 10, 11).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, de-endothelialization reversed the impairment in vascular reactivity observed in cirrhotic rats with BT, indicating that the vasoactive factor acting as the source of NO is the endothelium, not the vascular smooth muscle. The observation that a blunted response to MTx persisted after de-endothelialization or incubation with L-NNA has been made before (4,56). This reduced response is probably due to structural changes in the vessel wall, which are known to be induced by the chronic high blood flow and plasma-volume expansion (57) conditions present in cirrhosis and portal hypertension.…”

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confidence: 99%

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Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Wiest

Das²,

Cadelina³

et al. 1999

J. Clin. Invest.

281

184

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Nitric oxide (NO) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis. Bacteria, potent activators of NO and TNF-α synthesis, are found in the mesenteric lymph nodes (MLNs) of ascitic cirrhotic rats. Here, we investigated the impact of bacterial translocation (BT) to MLNs on TNF-α production, vascular NO release, and contractility in the mesenteric vasculature of ascitic cirrhotic rats. Vascular response to the α-adrenoagonist methoxamine, which is diminished in the superior mesenteric arterial beds of cirrhotic rats, is further blunted in the presence of BT. BT promoted vascular NO release in cirrhotic rats, an effect that depended on pressure-induced shear stress and was blocked by the NO inhibitor N ω -nitro-L-arginine. Removing the endothelium had the same effect. Endothelial NO synthase (eNOS), but not the inducible isoform (iNOS), was present in mesenteric vasculature of cirrhotic rats with and without BT, and its expression was enhanced compared with controls. TNF-α was induced in MLNs by BT and accumulated in parallel in the serum. This TNF-α production was associated with elevated levels of tetrahydrobiopterin (BH 4 ), a TNF-α-stimulated cofactor and enhancer of eNOSderived NO biosynthesis and NOS activity in mesenteric vasculature. These findings establish a link between BT to MLNs and increased TNF-α production and elevated BH 4 levels enhancing eNOSderived NO overproduction, further impairing contractility in the cirrhotic mesenteric vasculature.J. Clin. Invest. 104:1223-1233. mals subjected to experimental portal hypertension (41)(42)(43)(44). TNF-α is also known to be involved in the pathogenesis of the hyperdynamic circulatory syndrome in portal hypertension (42,45). Finally, the gut and its associated lymphoid tissue, the largest immunologic organ of the body, has recently been shown to produce and release TNF-α in response to BT, even in the absence of portal or systemic spread of bacteria (46,47).We designed this study to determine (a) whether there is any relationship between BT to MLNs and vascular contractility in the superior mesenteric arterial bed in cirrhosis; (b) if so, whether this additional vascular impairment is also due to vascular NO release; and (c) if that is the case, what NOS isoform is responsible for this additional NO overproduction and by what mechanism this NOS isoform is upregulated; and (d) whether TNF-α is playing any role in this process. MethodsAll experimental procedures in this study were conducted according to the American Physiological Society principles for the care and use of laboratory animals.Induction of liver cirrhosis in rats by CCl 4. Male SpragueDawley rats (Harlan Sprague Dawley Inc., Indianapolis, Indiana, USA), weighing 100-125 g, underwent inhalation exposure to CCl 4 and had phenobarbital (0.35g/L) added to their drinking water, as described previously by ourselves and others (4,5). This protocol produces a high yield of micronodular cirrhosis in about 12-16 we...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Wiest

Das²,

Cadelina³

et al. 1999

J. Clin. Invest.

281

184

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“…Additional experiments were performed after endothelial denudation. The denudation was achieved by combined treatment with cholic acid and distilled water as previously described [27] . In brief, after cannulation of the SMA and gentle flushing with 10 ml of warmed Krebs solution to eliminate blood, the mesentery was perfused with 1.5 ml of 0.5 % cholic acid for 10 s followed by 15 ml of warmed Krebs solution.…”

Section: In Vitro Mesenteric Perfusionmentioning

confidence: 99%

Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats

Ai¹,

Yang²,

Qiu³

et al. 2003

WJG

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AIM:To examine the participation of HSP90 in portal hypertensive rat mesentery in vitro. METHODS:Immunohistochemistry and Western-blot were used to examine the expression of HSP90 in mesenteric vasculature. HSP90 mRNA was detected by RT-PCR, and the role of HSP90 in hyperdynamic circulation was examined by in vitro mesenteric perfusion studies. RESULTS:HSP90 was overexpressed in endothelium of mesentery vasculature in animals with experimental portal hypertension induced by partial portal vein ligation (PVL) compared with normal animals. Geldanamycin (GA), a special inhibitor of HSP90 signaling, attenuated ACh-dependent vasodilation but did not affect vasodilation in response to sodium nitroprusside in normal rats. In PVL animals, the perfused mesentery was hyporesponsive to vasoconstrictor methoxamine. GA significantly potentiated methoxamineinduced vasoconstrictor after PVL.CONCLUSION: HSP90 plays a key role in NO-dependent hyperdynamic circulation in portal hypertension and provides a novel method for future treatment of portal hypertension.Ai JH, Yang Z, Qiu FZ, Zhu T. Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats. World

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“…However, the determination of the NOS isoform and the cell type responsible for the increase in NO has not reached a consensus. [83][84][85][86] NO and the Liver Microcirculation in Chronic Liver Diseases.…”

Section: Pathogenesis Of Portal Hypertensionmentioning

confidence: 99%

The hepatic circulation in health and disease: Report of a single-topic symposium

et al. 1998

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Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis

Cited by 84 publications

References 3 publications

Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats

The hepatic circulation in health and disease: Report of a single-topic symposium

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