Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats

Fernández, Mercedes; García‐Pagán, Juan Carlos; Casadevall, María; Bernadich, Cristina; Piera, Carlos; Whittle, Brendan J.R.; Piqué, Josep M.; Bosch, Jaume; Rodés, Juan

doi:10.1016/0016-5085(95)90698-3

Cited by 125 publications

(64 citation statements)

References 39 publications

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“…Moreover, in the PHT vasculature and stomach, enzyme activity of NOS2 is not increased 10,22 and dexamethasone, an NOS2 inhibitor, does not affect the PHT hyperdynamic circulation. 34 In contrast to NOS2, NOS3 enzyme activity is increased in PHT vasculature and stomach. 10,22 Although in vitro administration of TNF-␣ may induce destabilization of NOS3 mRNA, 45 in the present study anti-TNF-␣ treatment in vivo reversed NOS3 mRNA overexpression and normalized the increased mucosal blood flow in PHT gastric mucosa.…”

Section: Discussionmentioning

confidence: 97%

“…NOS activity was measured by determining the conversion of L-[ 3 H]arginine to [ 3 H]citrulline according to the method described by Fernandez et al 34 Frozen gastric specimens obtained from rats that had undergone surgery were homogenized with a Polytron homogenizer (Kinematica AG) in a buffer (250 mg/mL) containing 320 mmol/L sucrose; 0.1 mmol/L EDTA; 10 mmol/L HEPES, pH 7.4; 1 mmol/L DL-dithiothreitol; 10 µg/mL leupeptin; and 2 µg/mL aprotinin. The homogenates were then centrifuged (14,000 rpm for 20 minutes at 4°C), and protein normalized supernatants were assayed in duplicate.…”

Section: Rna Isolation and Reverse Transcription-polymerase Chain Reamentioning

confidence: 99%

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Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

et al. 1998

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Anti-tumor necrosis factor ␣ (TNF-␣) treatment decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric oxide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is responsible for the increased susceptibility of the mucosa to damage. In the present study, we examined whether TNF-␣ is overexpressed in portal hypertensive gastric mucosa and whether anti-TNF-␣ treatment affects gastric NOS3 messenger RNA (mRNA) and protein expression. We examined plasma concentrations of TNF-␣ and its protein expression in gastric specimens from portal hypertensive and sham-operated rats using Western blotting and immunohistochemistry. We also measured gastric mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-␣-neutralizing antibody treatment. The TNF-␣ protein levels in portal hypertensive stomachs were significantly increased by 57% compared with levels in sham-operated controls. TNF-␣ antibody treatment normalized gastric mucosal blood flow in portal hypertensive stomachs and significantly reversed overexpression of gastric NOS3 mRNA, protein, and its enzyme activity in portal hypertensive rats by 48%, 45%, and 33%, respectively. These results suggest that TNF-␣ may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-␣ treatment may ameliorate the pathophysiological abnormalities of portal hypertensive gastric mucosa. (HEPATOLOGY 1998;27: 906-913.)Portal hypertensive (PHT) gastropathy is now recognized as a clinical entity that is frequently seen in patients with portal hypertension. 1-3 The PHT gastric mucosa has distinct morphological and functional abnormalities that increase its susceptibility to damage by noxious factors such as alcohol, aspirin, and ischemia/reperfusion. [4][5][6][7][8][9] We have recently showed that nitric oxide synthase isoform 3 (NOS3) messenger RNA (mRNA) and protein are overexpressed in PHT gastric mucosa of rats, and this overexpression may be, at least in part, responsible for the increased susceptibility of PHT gastric mucosa to damage. 10

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Section: Discussionmentioning

confidence: 97%

Section: Rna Isolation and Reverse Transcription-polymerase Chain Reamentioning

confidence: 99%

Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

et al. 1998

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“…Nitric oxide synthase activity was measured by determining the conversion of 14 C-labeled L-arginine to 14 C-labeled L-citrulline, according to a previously reported method 22,23 in livers with cirrhosis treated with vehicle (n ϭ 10) or BH 4 (n ϭ 10). Briefly, rat livers were quickly dissected, blotted, weighed, and cut into small pieces.…”

Section: Methodsmentioning

confidence: 99%

The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis

et al. 2006

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In cirrhosis, intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension. Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH 4 ) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis. Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH 4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl 4 cirrhosis. Thereafter, rats were treated with tetrahydrobiopterin, and eNOS activity, NO bioavailability, assessed with a functional assay, and the vasodilator response to acetylcholine (endothelial function) were evaluated. Livers with cirrhosis showed reduced BH 4 levels and decreased GTPcyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine. Tetrahydrobiopterin supplementation increased BH 4 hepatic levels and eNOS activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis. In conclusion, the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the eNOS cofactor, tetrahydrobiopterin. Tetrahydrobiopterin supplementation improved the endothelial dysfunction of cirrhotic livers. (HEPATOLOGY 2006;44:44-52.)

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“…Interestingly, inducible NOS expression was also not detected within the hyperemic vasculature of these portal hypertensive animals, an observation that is consistent with a further lack of a proinflammatory induced response in these vessels. 4,10,40 Therefore, it seems that the enhanced PGI 2 levels in PHT animals are partially caused by differential changes in Cox-I mediated PGI 2 synthesis, and not by an induction of Cox-II, within specific vascular beds.…”

Section: Discussionmentioning

confidence: 97%

Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: Role in the hyperdynamic circulation†

et al. 1998

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Portal hypertension (PHT) is characterized by splanchnic hyperemia due to enhanced production of vasodilator substances. Enhanced vasodilation and increased splanchnic blood flow contribute to the elevated portal pressure characteristic of PHT. The aim of this study was to determine whether cyclooxygenase (Cox) expression is altered in PHT vessels and whether chronic inhibition of this enzyme impacts on splanchnic blood flow in PHT. PHT was created in Sprague-Dawley rats by a partial portal vein ligation. Control animals were sham operated. Plasma 6-keto-PGF 1 ␣ (prostaglandin F 1 ␣) levels were significantly elevated in PHT after 2 days as compared with sham and remained elevated up to day 15. Treatment with indomethacin (2 mg/kg ip daily for 15 days) resulted in a significant decrease in 6-keto-PGF 1 ␣ levels, which was concomitant with a significant decrease in superior mesenteric artery blood flow (Qsma) after 15 days in PHT rats. Cox-I expression was differentially enhanced in the PHT superior mesenteric artery and thoracic aorta during the development and progression of PHT. In contrast, Cox-II messenger RNA (mRNA) and protein expression was not detected in either of these vessels throughout the development of PHT. These data suggest that PHT is associated with enhanced Cox-I expression within the splanchnic vasculature concomitant with elevated plasma prostacyclin levels and a significant pressor response to indomethacin in PHT animals. We conclude that enhanced Cox-I expression results in increased prostacyclin levels that partially contribute to the maintenance of the hyperemia typical of PHT. (HEPATOLOGY 1998;27:20-27.)Portal hypertension (PHT) is characterized by a hyperdynamic circulatory state which is commonly observed in patients with chronic liver disease and in experimental models of PHT with extensive collateral circulation. 1,2 The main pathophysiological change of the hyperdynamic circulation is a generalized reduced vascular resistance. 1,2 The reasons for the decreased vascular resistance include exaggerated endothelial function with enhanced synthesis and/or release of vasoactive substance, such as prostacyclin and nitric oxide (NO), and altered vascular responsiveness to vasoconstrictor substances, such as vasopressin, angiotensin, norepinephrine, and methoxamine. 3-6 NO, a potent endothelium-derived relaxing factor, is one of the major vasoactive substances implicated in the pathogenesis of the reduced vascular resistance in PHT. 7,8 PHT is associated with enhanced nitric oxide synthase (NOS) activity within the hyperemic vasculature. 4,9,10 Moreover, the altered vascular responsiveness and circulatory abnormalities of PHT are in part corrected following inhibition of NOS with specific NOS inhibitors. 11,12 While the enhanced NO production may be a major modulator of the altered vascular response in PHT, other vasodilator substances may also be involved inasmuch as acute blockade of NOS activity fails to completely reverse the hyperdynamic circulation. 13,14 The production of prostacycli...

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Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats

Cited by 125 publications

References 39 publications

Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis

Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: Role in the hyperdynamic circulation†

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