Gastroenterology

Gastroenterology

Volume 119, Issue 1, July 2000, Pages 196-200
Gastroenterology

Liver, Pancreas, and Biliary Tract
Role of aortic nitric oxide synthase 3 (eNOS) in the systemic vasodilation of portal hypertension,☆☆

https://doi.org/10.1053/gast.2000.8554Get rights and content

Abstract

Background & Aims: In portal hypertension, the mechanisms responsible for nitric oxide (NO) overproduction and vasodilation have not yet been clearly identified. One hypothesis is that NO synthase (NOS) 3 is overactivated because of shear stress in endothelial cells caused by hyperkinetic circulation. The aim of this study was to evaluate aortic NOS3 after a reduction of blood flow by long-time β-adrenoceptor antagonist administration. Methods: Propranolol or atenolol was administered by gavage in portal vein–stenosed and sham-operated rats. The vascular reactivity of thoracic aortic rings to phenylephrine, total aortic NOS activity, and aortic NOS3 messenger RNA and protein expressions were studied. Results: After propranolol or atenolol administration, the aortic hyporesponse returned to normal in portal vein–stenosed rats. Total aortic NOS activity was higher in portal vein–stenosed aortas and significantly decreased after β-blocker administration. Aortic NOS3 expressions were more marked in portal vein–stenosed aortas than in controls, but NOS3 expressions were reduced after propranolol administration. Conclusions: In portal hypertension, aortic NOS3 activity and expressions are enhanced but return to normal after β-blocker administration. These results suggest that in portal hypertension, increased shear stress, related to high blood flow, induces enhanced aortic NOS3.

GASTROENTEROLOGY 2000;119:196-200

Section snippets

Animals

Male Sprague–Dawley rats (Charles River Laboratories, Saint-Aubin-Lès-Elbeuf, France) were divided into 2 groups. One group included 49 rats that underwent portal vein stenosis to induce portal hypertension, as described previously.10 Portal hypertension was considered to be present 14 days after surgery in portal vein–stenosed rats. A second group included 40 rats that underwent sham operations (sham-operated group) under pentobarbital anesthesia. Studies were performed in rats weighing

Results

Concentration-response curves were significantly lower in aortas from untreated portal hypertensive rats than in those from untreated sham-operated rats (Figure 1).

. Concentration-response curves to phenylephrine in isolated thoracic aortic rings from sham-operated (○) and portal vein–stenosed (●) rats. P < 0.05 between sham-operated and portal vein–stenosed rats.

After propranolol or atenolol administration in portal hypertensive rats, aortic concentration-response curves were significantly

Discussion

Evidence of increased NO production has been found in several models of portal hypertension with or without cirrhosis.3, 4 In these models, in vitro hyporeactivity to vasoconstrictors has been shown in aortas and the superior mesenteric artery from cirrhotic and portal vein–stenosed rats and was abolished by NO inhibition.2 These results suggest that NO overproduction is a major factor of systemic arterial vasodilation in portal hypertension. An increase in cytokines and endotoxin has been

Acknowledgements

The authors thank Dr. Fabienne Pessione and Dr. J. Paries for expert statistic advice and L. Font and A. Truskolasky for expert technical assistance.

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Address requests for reprints to: Didier Lebrec, M.D., INSERM Unité 481, Hôpital Beaujon, 92118 Clichy, France. e-mail: [email protected]; fax: (33) 1-47-30-17-11.

☆☆

Supported in part by Ferring SA France; Fondation pour la Recherche Médicale (to D.P.); and the Fondation Nationale Alfred Kastler and Ernst und Berta Grimmke-Stiftung (to J.H.).

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