title: Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation.
abstract: Advanced age is associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed central event is diminished amounts of nitric oxide (NO) due to reduced generation by endothelial NO synthase (eNOS) and increased oxidative stress. In addition, it is widely accepted that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10-15mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased insulin responses, reduced plasma creatinine as well as improved endothelial relaxation to acetylcholine and attenuated contractility to ANG II in resistance arteries. Mechanistically, nitrate reduced NADPH oxidase-mediated oxidative stress in the cardiovascular system and increased cGMP signaling. Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate for age-related disturbances in endogenous NO generation via inhibition of NADPH oxidase and modulation of ANG II receptor expression. These novel findings may have implications for nutrition-based preventive and therapeutic strategies against cardiovascular and metabolic diseases.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden. Electronic address: mihezel@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Hezel
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Peleli
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Christa
authors.initials: C
authors.lastname: Zollbrecht
authors.affiliation: Department of Cardiovascular and Renal Research, University of Southern Denmark, DK-5230 Odense, Denmark.
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Checa
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Alessia
authors.initials: A
authors.lastname: Giulietti
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden. Electronic address: Mattias.Carlstrom@ki.se.
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlström
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D006152:Cyclic GMP / Q000097:blood; D019587:Dietary Supplements; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D009566:Nitrates / Q000008:administration & dosage* / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000097:blood / Q000235:genetics; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000097:blood* / Q000235:genetics; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D009566:Nitrates; D009573:Nitrites; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; D006152:Cyclic GMP; D000109:Acetylcholine
keywords: Aging; Angiotensin II receptors; Endothelial dysfunction; Hypertension; Metabolic syndrome; NADPH oxidase; Nitric oxide; Nitrite; Renin; Superoxide