title: The direct renin inhibitor aliskiren improves vascular remodelling in transgenic rats harbouring human renin and angiotensinogen genes.
abstract: In the present study, we tested the hypothesis that chronic treatment with the direct rennin inhibitor aliskiren improves the remodelling of resistance arteries in dTGR (double-transgenic rats). dTGR (5 weeks) were treated with aliskiren (3 mg/kg of body mass per day) or ramipril (1 mg/kg of body mass per day) for 14 days and compared with age-matched vehicle-treated dTGR. BP (blood pressure) was similarly reduced in both aliskiren-treated and ramipril-treated rats compared with control dTGR (167±1 and 169±2 mmHg compared with 197±4 mmHg respectively; P<0.05). The M/L (media-to-lumen) ratio assessed on pressurized preparations was equally reduced in aliskiren-treated and ramipril-treated rats compared with controls (6.3±0.5 and 6.4±0.2% compared with 9.8±0.4% respectively; P<0.05). Endothelium-dependent and -independent relaxations were similar among the groups. L-NAME (N(G)-nitro-L-arginine methyl ester) significantly reduced acetylcholine-induced dilation in drug-treated dTGR. This effect was significantly more prominent in aliskiren-treated rats. eNOS (endothelial NO synthase) expression showed a 2-fold increase only in aliskiren-treated dTGR as compared with controls (P<0.01) and ramipril-treated dTGR (P<0.05). Plasma nitrite, as an index of NO production, was significantly increased in dTGR treated with either aliskiren or ramipril compared with controls. Only aliskiren induced a 2-fold increase in plasma nitrite, which was significantly greater than that induced by ramipril (P<0.05). gp91(phox) expression and ROS (reactive oxygen species) production in aorta were significantly and similarly reduced by both drugs. In conclusion, equieffective hypotensive doses of aliskiren or ramipril reduced the M/L ratio of mesenteric arteries and improved oxidative stress in dTGR. However, only aliskiren increased further NO production in the vasculature. Hence, in dTGR, direct renin inhibition induces favourable effects similar to that induced by ACE (angiotensin-converting enzyme) inhibition in improving vascular remodelling through different mechanisms.
authors: Division of Cardiology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy. savoiac@yahoo.it
authors: Carmine
authors: C
authors: Savoia
authors: Emanuele
authors: E
authors: Arrabito
authors: Rosa
authors: R
authors: Parente
authors: Lidia
authors: L
authors: Sada
authors: Luca
authors: L
authors: Madaro
authors: Carmine
authors: C
authors: Nicoletti
authors: Luigi
authors: L
authors: Zezza
authors: Alessandro
authors: A
authors: Alonzo
authors: Speranza
authors: S
authors: Rubattu
authors: Serena
authors: S
authors: Michelini
authors: Dominik N
authors: DN
authors: Muller
authors: Massimo
authors: M
authors: Volpe
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics*; D014655:Vascular Resistance; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D005650:Fumarates; D009569:Nitric Oxide; D017257:Ramipril; D017382:Reactive Oxygen Species; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren