Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis.
Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.
Fernández-Varo
Guillermo
G
Hormonal Laboratory, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona and Instituto Reina Sofia de Investigaciones Nefrológicas, Barcelona, Spain.
Ros
Josefa
J
Morales-Ruiz
Manuel
M
Cejudo-Martín
Pilar
P
Arroyo
Vicente
V
Solé
Manel
M
Rivera
Francisca
F
Rodés
Juan
J
Jiménez
Wladimiro
W
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001158:Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001201:Ascites / Q000201:enzymology / Q000503:physiopathology; D001775:Blood Circulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester