Arginase inhibition alleviates hypertension in the metabolic syndrome

H M El-Bassossy, R El-Fawal, A Fahmy, Malcolm L Watson

Research output: Contribution to journalArticle

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Abstract

Background and purpose:
We have previously shown that arginase inhibition alleviates hypertension associated with in a diabetic animal model. Here we investigated the protective effect of arginase inhibition on hypertension in metabolic syndrome.

Experimental approach:
Metabolic syndrome was induced in rats by administration of fructose (10% in drinking water) for 12 weeks to induce vascular dysfunction. Three arginase inhibitors (citrulline, norvaline and ornithine) were administered daily in the last 6 weeks of study before and tail blood pressure (BP) was recorded in conscious animals. Concentration response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) in addition to ACh-induced NO generation were obtained in thoracic aorta rings. Serum glucose, insulin, uric acid and lipid profile were determined as well as reactive oxygen species (ROS) and arginase activity.

Key results:
Arginase activity was elevated in metabolic syndrome while significantly inhibited by citrulline, norvaline or ornithine treatment. Metabolic syndrome was associated with elevations in systolic and diastolic BP, while arginase inhibition significantly reduced elevations in diastolic and systolic BP. Metabolic syndrome increased vasoconstriction responses of aorta to PE and KCl and decreased vasorelaxation to ACh, while arginase inhibition completely prevented impaired responses to ACh. In addition, arginase inhibition prevented impaired NO generation and exaggerated ROS formation in metabolic syndrome. Furthermore, arginase inhibition significantly reduced hyperinsulinemia and hypertriglyceridemia without affecting hyperuricemia or hypercholererlimia associated with metabolic syndrome.

Conclusions and Implications:
arginase inhibition alleviates hypertension in metabolic syndrome directly through endothelial-dependent relaxation/NO signaling protection and indirectly through inhibition of insulin resistance and hypertriglyceridemia.
Original languageEnglish
Pages (from-to)693-703
Number of pages11
JournalBritish Journal of Pharmacology
Volume169
Issue number3
Early online date15 May 2013
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Diabetes
  • vascular dysfunction

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