Synergistic effect of angiotensin II and nitric oxide synthase inhibitor in increasing aortic stiffness in mice

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 290; no. 3; pp. H1190 - H1198
• Main Authors: Fitch, Richard M, Rutledge, John C, Wang, Yi-Xin, Powers, Andrew F, Tseng, Jih-Lie, Clary, Taegan, Rubanyi, Gabor M
• Format: Journal Article
• Language: English
• Published: United States 01.03.2006
• Subjects: Angiotensin II - administration & dosage; Animals; Aorta - drug effects; Aorta - physiology; Drug Combinations; Drug Synergism; Elasticity; Male; Mice; Mice, Inbred C57BL; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; NG-Nitroarginine Methyl Ester - administration & dosage; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Stress, Mechanical; Vascular Resistance - drug effects; Vascular Resistance - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00327.2005

1 Department of Pharmacology, Berlex Biosciences, Richmond; 2 Department of Internal Medicine, School of Medicine, University of California at Davis, Davis; and 3 Department of Gene Therapy, Berlex Biosciences, Richmond, California Submitted 4 April 2005 ; accepted in final form 26 October 2005 Although they are implicated on their own as risk factors for cardiovascular disease, the potential link between nitric oxide (NO) deficiency, ANG II, and vascular stiffening has not been tested before. We evaluated the role of chronic ANG II treatment and NO deficiency, alone and in combination, on aortic stiffness in mice and tested parameters contributing to increases in active or passive components of vascular stiffness, including blood pressure, vascular smooth muscle contractility, and extracellular matrix components. Untreated (control) mice and mice treated with a NO synthase (NOS) inhibitor [ N -nitro- L -arginine methyl ester ( L -NAME), 0.5 g/l] were implanted with osmotic minipumps delivering ANG II (500 ng·kg –1 ·min –1 ) for 28 days. Aortic stiffness was then measured in vivo by pulse wave velocity (PWV) and ex vivo by load-strain analysis to obtain values of maximal passive stiffness (MPS). Blood pressure and aortic contractility ex vivo were measured. ANG II treatment or NOS inhibition with L -NAME did not independently increase vascular stiffness; however, the combined treatments worked synergistically to increase PWV and MPS. The combined treatments of ANG II + L -NAME also significantly increased aortic wall collagen content while decreasing elastin. These novel results suggest that NO deficiency and ANG II act synergistically to increase aortic stiffness in mice predominantly via changes in aortic wall collagen/elastin ratio. blood pressure; vascular smooth muscle; collagen; elastin; N -nitro- L -arginine methyl ester Address for reprint requests and other correspondence: G. M. Rubanyi, Dept. of Gene Therapy, Berlex Biosciences, 2600 Hilltop Dr., Richmond, CA 94804-0099 (e-mail: gabor_rubanyi{at}berlex.com )