Enhanced nitric oxide synthase activity in portal hypertensive rabbits

Cahill, Paul A.; Foster, Cory; Redmond, Eileen M.; Gingalewski, Cindy; Wu, Yuping; Sitzmann, James V.

doi:10.1002/hep.1840220233

Cited by 58 publications

(55 citation statements)

References 29 publications

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“…17 ET-1 also decreased Qsma in both sham and PHT animals; however, the percent change from baseline for the peak response was not significantly different in PHT animals as compared with sham, despite an increase in the contractile response of the superior mesenteric artery to increasing concentrations of ET-1 in vitro and an increase in the expression of ET-A and ET-B receptors in these vessels. Because endothelial NO production is enhanced in PHT animals, 38,39 it is likely that the hyperactivity to ET-1 may be offset by the pronounced NO-induced vasodilation in this vascular bed in PHT. Thus, an equilibrium between the NO and ET systems may dictate the responsiveness of the hyperemic vessel to ET-1 in vivo.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

et al. 1998

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Portal hypertension (PHT) is characterized by a hyperdynamic circulatory state that is commonly observed in patients with chronic liver disease and in experimental models of PHT with extensive collateral circulation. 1,2 Experimental models have improved our understanding of the pathophysiology of PHT. 1,2 It is now clear that an increased vascular resistance to portal flow is the initial factor responsible for the increase in portal pressure due to changes in hepatic circulation. 1,2 In the latter stages of the development of PHT, an increased portal venous blood inflow, promoted by splanchnic vasodilation, contributes to the maintenance and aggravation of PHT. 1,2 The splanchnic circulation is therefore the vascular bed with the most pronounced vasodilation, although there is also hyperkinetic syndrome systemically with reduced arterial pressure and peripheral vascular resistance. 1,2 An expanded plasma volume is also apparent in PHT and represents another mechanism that further contributes to the increased portal pressure. 3,4 Endothelin (ET) is a 21-amino acid peptide with potent vasoconstrictive and mitogenic properties. 5,6 ET is produced by several cell types including vascular endothelial cells. The cellular action of ET on vascular tissue is initiated by peptide binding to specific cell surface receptors. Two different receptors for ET have been identified: cloned and characterized. 7,8 The ET-A receptor on vascular tissue, which preferentially binds ET-1, is linked to phospholipase C enzyme activity, subsequent phosphoinositide metabolism, and the mobilization of intracellular calcium via a Gq protein. [5][6][7][8][9][10] The ET-B receptor, which equally binds ET-1 and ET-3, respectively, is functionally coupled to nitric oxide (NO) synthase activity via an inhibitory G-protein (Gi) on endothelial cells and coordinates the generation of NO via a tyrosine kinasedependent and a calcium/calmodulin-dependent pathway. 5,6,9,11 ET-B receptors are also present on vascular smooth muscle cells and have been shown to mediate vasoconstriction in veins 12,13 and some arteries. [14][15][16] The possible role of ET in the pathophysiology of PHT has recently been addressed in humans and animal models of PHT with or without parenchymal dysfunction. [17][18][19][20][21][22][23][24] While an overwhelming number of clinical studies have demonstrated increased ET levels in cirrhotic patients, 20,21 several studies have also reported decreased circulating levels of ET-1 in PHT. 22,23 Therefore, the pathophysiological importance of ET in PHT remains unclear. A reduced pressor responsiveness to high doses of ET in cirrhotic rats with PHT has been reported. 24 This hyporesponsiveness to ET-1 appears to be dependent on NO production and may contribute to the maintenance of splanchnic blood flow in these animals. However, the role of endogenous ET in controlling splanchnic hemodynamics in PHT has not been evaluated. Of note, studies in cirrhotic rats and PHT animals have demonstrated that ET receptors are up-regulated in the ki...

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Section: Discussionmentioning

confidence: 99%

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

et al. 1998

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“…In a rabbit model of portal hypertension (partial portal vein ligation [PVL]), administration of L-NAME results in a 40% reduction in splanchnic blood flow in the portal hypertensive animal compared with only a 27% decrease in control. 91 In vitro, there is a greater relaxation in response to Ach in aortic rings isolated from portal hypertensive rats compared with controls, suggesting that there is an augmentation of NO in these vessels. Using the citrulline conversion assay, there is an increase in the amount and/or functional activity of calcium-dependent NOS in the particulate fraction of the superior mesenteric artery of portal hypertensive animals compared with normal.…”

Section: Pathogenesis Of Portal Hypertensionmentioning

confidence: 95%

“…Using the citrulline conversion assay, there is an increase in the amount and/or functional activity of calcium-dependent NOS in the particulate fraction of the superior mesenteric artery of portal hypertensive animals compared with normal. 91 Nicotinamide adenine dinucleotide phosphate diaphorase histochemical staining shows that this activity occurs in the endothelium of vessels rather than the smooth muscle. 91 These studies and others suggest that eNOS is the isoform responsible for the splanchnic hyperemia observed in portal hypertension.…”

Section: Pathogenesis Of Portal Hypertensionmentioning

confidence: 99%

“…91 Nicotinamide adenine dinucleotide phosphate diaphorase histochemical staining shows that this activity occurs in the endothelium of vessels rather than the smooth muscle. 91 These studies and others suggest that eNOS is the isoform responsible for the splanchnic hyperemia observed in portal hypertension. 83,84,91,92 However, whether this increase in eNOS in portal hypertension is a pathogenic factor in the development of the hyperdynamic circulation or is a result of the increased flow and shear stress associated with the hyperdynamic circulation remains unresolved.…”

Section: Pathogenesis Of Portal Hypertensionmentioning

confidence: 99%

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

et al. 1998

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“…NOS activity was determined in aortic tissue 5 hours after LPS or saline were injected intravenously as described in Experiment 1. NOS activity was measured by determining the conversion of L[ 14 C] arginine to L[14-C] citrulline based on the modified method from Bredt et al 39 and Cahill et al 18,19 Rats were anesthetized with pentobarbital. The thoracic aorta was resected, and adherent fat was removed.…”

Section: Animalsmentioning

confidence: 99%

Abnormal regulation of aortic NOS2 and NOS3 activity and expression from portal vein-stenosed rats after lipopolysaccharide administration

et al. 1999

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Hyporeactivity to vasoconstrictors in aortae from portal vein-stenosed rats is associated with an increased activity of endothelial NO synthase (NOS3). In contrast, during sepsis, which is common in cirrhosis, vascular hyporeactivity is associated with an induction of inducible NOS2. The aim of this study was to investigate the in vitro reactivity to phenylephrine and the regulation of NOS2 and NOS3 in aortae from portal vein-stenosed rats after lipopolysaccharide (LPS) administration. Aortic vascular reactivity for phenylephrine, aortic NOS activity, and NOS2 and NOS3 protein expression were determined 5 hours after intravenous LPS or saline administration. Moreover, aortic NOS activity was measured after 5-hour in vitro incubation in LPS. LPS induced a significantly smaller decrease in aortic tension in portal vein-stenosed than in sham-operated rats. Under baseline conditions, aortic NOS activity and NOS3 protein expression were higher in portal vein-stenosed than in sham-operated rats, and NOS2 protein expression was not detected in aortae from either group. After LPS administration, NOS activity and NOS2 protein expression increased significantly less in portal vein-stenosed than in sham-operated rat aortae. Similar results were obtained after in vitro incubation with LPS. Endothelium removal or NOS3 inhibition with the calmodulin inhibitor, W7, increased NOS activity in the aortae of portal vein-stenosed rats after LPS incubation. In conclusion, in aortae of portal vein-stenosed rats exposed to LPS, no further decrease in aortic reactivity to phenylephrine was observed, and the induction of NOS2 was down-regulated. Endothelium removal or calmodulin inhibition inhibits NOS3 overactivity and leads to normalized NOS2 activation after LPS in aortae from portal vein-stenosed rats. (HEPATOLOGY 1999;30:698-704.)In cirrhosis, the occurrence of sepsis and the morbidity and mortality of septic shock are increased in humans and animal models. 1-4 Vasodilation in septic shock or during endotoxemia is caused part by an overproduction of nitric oxide (NO), which in this case is synthesized by the inducible NO synthase isoform (NOS2). [5][6][7][8][9][10] On the other hand, a hyperdynamic syndrome that results in systemic and splanchnic vasodilation, 11-13 a decreased responsiveness to vasoconstrictors, [14][15][16] and an increased cardiac output is also observed in portal hypertension with or without liver disease. In contrast to the hypothesis by Vallance and Moncada, 17 who suggested that circulating bacterial endotoxins induced vascular NOS2 in patients with cirrhosis, there is increasing evidence that the overproduction of NO in aortae of rats with extrahepatic portal hypertension 18-20 and cirrhotic rats without ascites [21][22][23] is caused by increased endothelial, constitutive NO synthase (NOS3) expression and activity without NOS2 induction. [23][24][25] In fact, because bacterial infections and sepsis are frequent in cirrhosis, NO overproduction in relation to both NOS3 overactivity and NOS2 induction may occ...

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Enhanced nitric oxide synthase activity in portal hypertensive rabbits

Cited by 58 publications

References 29 publications

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

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

Abnormal regulation of aortic NOS2 and NOS3 activity and expression from portal vein-stenosed rats after lipopolysaccharide administration

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