Synergistic effect of angiotensin II and nitric oxide synthase inhibitor in increasing aortic stiffness in mice.
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(omega)-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.
Fitch
Richard M
RM
Department of Pharmacology, Berlex Biosciences, 2600 Hilltop Dr., Richmond, California 94804-0099, USA.
Rutledge
John C
JC
Wang
Yi-Xin
YX
Powers
Andrew F
AF
Tseng
Jih-Lie
JL
Clary
Taegan
T
Rubanyi
Gabor M
GM
D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D004338:Drug Combinations; D004357:Drug Synergism; D004548:Elasticity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D013314:Stress, Mechanical; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D004338:Drug Combinations; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester