Inhibition of oxidative stress and improvement of endothelial function by amlodipine in angiotensin II-infused rats

Background: Calcium channel blockers such as amlodipine are effective antihypertensive agents. In this study we investigated the effects of amlodipine on vascular oxidative stress, expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1), and endothelial function in angiotensin (Ang) II-infused rats. Methods: Sprague-Dawley rats were treated with Ang II (0.7 mg/kg/day subcutaneously injected by mini-pump), with or without amlodipine (10 mg/kg/day by gavage), for 5 days and compared with control rats. Levels of aortic ring superoxide (O₂^-) and peroxynitrite (ONOO^-) were determined, and systolic blood pressure (SBP) and endothelium-dependent relaxation were evaluated. Results: Compared with control rats, Ang II-infused rats developed hypertension (175 ± 3 v 135 ± 2 mm Hg, P < .05), aortic hypertrophy (16.9 ± 1.3 v 13.2 ± 0.3 mg/cm, P < .05), left ventricular hypertrophy (0.236 ± 0.003 v 0.204 ± 0.004 g/100 g body weight, P < .05), and impaired endothelium-dependent relaxation (ED₅₀: 6.6 ± 0.2 v 8.0 ± 0.2 -log mol/L acetylcholine concentration, P < .05). Compared with control rats, Ang II-infused rats also had higher aortic levels of LOX-1 mRNA expression, O₂^-production (1005 ± 140 v 608 ± 159 counts/min/mg, P < .05), ONOO^- production (1875 ± 295 v 782 ± 115 counts/min/mg, P < .05), and plasma free 8-F₂α-isoprostanes (67.4 ± 19.1 v 27.2 ± 6.1 pg/mL, P < .05). In Ang II-infused rats SBP, aortic hypertrophy, endothelial dysfunction, LOX-1 expression, aortic O₂^- and ONOO ^- production, and plasma free 8-F₂α-isoprostane levels were significantly reduced by amlodipine treatment. Conclusions: Amlodipine has antihypertensive and antioxidant activity in vivo, which effectively inhibits many of the oxidative stress-dependent mechanisms involved in Ang II-mediated cardiovascular injury.