title: Local renin-angiotensin system mediates endothelial dilator dysfunction in aging arteries.
abstract: Aging impairs endothelium-dependent NO-mediated dilatation, which results from increased production of reactive oxygen species (ROS). The local generation of angiotensin II (ANG II) is increased in aging arteries and contributes to inflammatory and fibrotic activity of smooth muscle cells and arterial wall remodeling. Although prolonged in vivo ANG II inhibition improves the impaired endothelial dilatation of aging arteries, it is unclear whether this reflects inhibition of intravascular or systemic ANG II systems. Experiments were therefore performed on isolated tail arteries from young (3-4 mo) and old (22-24 mo) F344 rats to determine if a local renin-angiotensin system contributes to the endothelial dilator dysfunction of aging. Aging impaired dilatation to the endothelial agonist acetylcholine but did not influence responses to a nitric oxide (NO) donor (DEA NONOate). Dilatation to acetylcholine was greatly reduced by NO synthase inhibition [nitro-l-arginine methyl ester (l-NAME)] in young and old arteries. In isolated arteries, acute inhibition of angiotensin-converting enzyme (ACE) (perindoprilat), renin (aliskiren), or AT1 receptors (valsartan, losartan) did not influence dilatation to acetylcholine in young arteries but increased responses in old arteries. After ANG II inhibition, the dilator response to acetylcholine was similar in young and old arteries. ROS activity, which was increased in endothelium of aging arteries, was also reduced by inhibiting ANG II (perindoprilat, losartan). Renin expression was increased by 5.6 fold and immunofluorescent levels of ANG II were confirmed to be increased in aging compared with young arteries. Exogenous ANG II inhibited acetylcholine-induced dilatation. Therefore, aging-induced impairment of endothelium-dependent dilatation in aging is caused by a local intravascular renin-angiotensin system.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Sheila
authors.initials: S
authors.lastname: Flavahan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Fumin
authors.initials: F
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland nflavah1@jhmi.edu.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Flavahan
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000375:Aging; D000577:Amides / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005650:Fumarates / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D000068756:Valsartan / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D000092502:Renin Inhibitors
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D005650:Fumarates; D007211:Indoles; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D010656:Phenylephrine; D000068756:Valsartan; D000092502:Renin Inhibitors; C053500:perindoprilat; C446481:aliskiren
keywords: AT1 receptors; aging; endothelium; keywords. angiotensin ii