Arginase inhibition alleviates hypertension in the metabolic syndrome

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 BP was recorded in conscious animals. Concentration response curves for phenylephrine (PE), KCl and 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 hyperinsulinaemia and hypertriglyceridaemia without affecting hyperuricaemia or hypercholesterolaemia associated with metabolic syndrome.

Conclusions and implications: Arginase inhibition alleviates hypertension in metabolic syndrome directly through endothelial-dependent relaxation/NO signalling protection and indirectly through inhibition of insulin resistance and hypertriglyceridaemia.

Figure 1

Effect of fructose-induced metabolic syndrome (M, 10% in drinking water, for 12 weeks) and daily oral administration (last 6 weeks) of citrulline (50 mg·kg⁻¹), norvaline (50 mg·kg⁻¹) or ornithine (200 mg·kg⁻¹) on serum arginase activity (A) or the effect of in vitro incubation with uric acid (400 μM, 1 h), citrulline (1 mM, 1 h) or arginine (1 mM, 1 h) on aortic arginase activity (B). *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control group values; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 compared with the corresponding M group values; by one-way anova and Newman–Keuls post hoc test.

Figure 2

Effect of fructose- induced metabolic syndrome (M, 10% in drinking water, for 12 weeks) and daily oral administration (last 6 weeks) of citrulline (50 mg·kg⁻¹), norvaline (50 mg·kg⁻¹) or ornithine (200 mg·kg⁻¹) on the systolic (A) and diastolic (B) blood pressure. *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control group values; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 compared with the corresponding M group values; by one-way anova and Newman–Keuls post hoc test.

Figure 3

Effect of fructose- induced metabolic syndrome (M, 10% in drinking water, for 12 weeks) and daily oral administration (last 6 weeks) of citrulline (50 mg·kg⁻¹), norvaline (50 mg·kg⁻¹) or ornithine (200 mg·kg⁻¹) on the isolated aorta responsiveness to PE (A), KCl (B) and ACh (C). Symbols indicate mean ± SEM for n = 6–8 animals; *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control group values; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 compared with the corresponding M group values; by one-way anova and Newman–Keuls post hoc test.

Figure 4

Effect of in vitro incubation with citrulline (1 mM, 1 h), norvaline (1 mM, 1 h) or ornithine (1 mM, 1 h) on the isolated metabolic syndrome (M) aorta responsiveness to PE (A), KCl (B) and ACh (C). Symbols indicate mean ± SEM for n = 6–8 animals; *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control group values; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 compared with the corresponding M group values; by one-way anova and Newman–Keuls post hoc test.

Figure 5

Effect of in vitro incubation with uric acid (200 μM, 1 h) with or without cirulline (1 mM, 1 h), norvaline (1 mM, 1 h) or ornithine (1 mM, 1 h) on the isolated normal aorta responsiveness to PE (A), KCl (B) and ACh (C) or on the isolated perfused kidney relaxation to ACh (D). Symbols indicate mean ± SEM for n = 6–8 animals; *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control group values; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 compared with the corresponding uric acid values; by one-way anova and Newman–Keuls post hoc test.

Figure 6

Effect of fructose- induced metabolic syndrome (M, 10% in drinking water, for 12 weeks) and chronic daily oral administration (last 6 weeks) of citrulline (50 mg·kg⁻¹), norvaline (50 mg·kg⁻¹) or ornithine (200 mg·kg⁻¹) on ACh-stimulated NO generation (A) and basal ROS formation (B). Symbols indicate mean ± SEM for n = 6–8 animals; *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control group values; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 compared with the corresponding M group values; by one-way anova and Newman–Keuls post hoc test.