title: Nifedipine attenuation of abdominal aortic aneurysm in hypertensive and non-hypertensive mice: Mechanisms and implications.
abstract: Rupture of abdominal aortic aneurysm (AAA) is a lethal event. No oral medicine has been available to prevent or treat AAA. We have recently identified a novel mechanism of eNOS uncoupling by which AAA develops, in angiotensin II (Ang II) infused hyperphenylalaninemia 1 (hph-1) mice. Using this unique model we investigated effects on AAA formation of the L-type calcium channel blocker nifedipine, in view of the unclear relationship between hypertension and AAA, and unclear mechanisms of aneurysm protective effects of some blood pressure lowering drugs. Six-month old hph-1 mice were infused with Ang II (0.7 mg/kg/day) for 2 weeks, and fed nifedipine chow at two different doses (5 and 20 mg/kg/day). While the high dose of nifedipine reduced blood pressure, the lower dose had no effect. Interestingly, the incidence rate of AAA dropped from 71% to 7 and 12.5% for low and high dose nifedipine, respectively. Expansion of abdominal aorta, determined by ultrasound imaging, was abolished by both doses of nifedipine, which recoupled eNOS completely to improve NO bioavailability. Both also abrogated aortic superoxide production. Of note, Ang II activation of NADPH oxidase in vascular smooth muscle cells and endothelial cells, known to uncouple eNOS, was also attenuated by nifedipine. Although low dose was a sub-pressor while the high dose reduced blood pressure via inhibition of calcium channels, both doses were highly effective in preventing AAA by preserving eNOS coupling activity to eliminate sustained oxidative stress from uncoupled eNOS. These data demonstrate that oral treatment of nifedipine is highly effective in preserving eNOS function to attenuate AAA formation. Nifedipine may be used for AAA prevention either at low dose in AAA risk group, or at high dose in patients with co-existing hypertension.
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90025, USA; School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xiao Niu
authors.initials: XN
authors.lastname: Miao
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Kin Lung
authors.initials: KL
authors.lastname: Siu
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90025, USA. Electronic address: hcai@mednet.ucla.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000804:Angiotensin II / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009543:Nifedipine / Q000008:administration & dosage*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010661:Phenylketonurias / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: D000959:Antihypertensive Agents; D020746:Calcium Channels, L-Type; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; D009543:Nifedipine
keywords: Abdominal aortic aneurysm; Angiotensin II; Blood pressure; NADPH oxidase (NOX); Nifedipine; eNOS recoupling; hph-1 mice