Inhibition of superoxide generation and improvement of endothelial function by amlodipine in angiotensin II induced hypertension

Abstract

Angiotensin II (Ang II) activates NADH/NADPH oxidase; this results in increased generation of superoxide anion (O2-) which has been linked to hypertension, vascular hypertrophy and reduced NO mediated endothelium dependent relaxation (EDR). Studies in vitro have suggested that the calcium channel blocker Amlodipine (AML) has anti-oxidant properties. Thus we investigated the effects of AML on aortic (Ao) O2- production, Ao hypertrophy as well as EDR in rats with Ang II induced hypertension. Sprague-Dawley rats were given vehicle (VEH), Ang II (0.7 mg/kg/day via osmotic mini-pump) or Ang II plus AML (AngII-AML, 10 mg/kg/day by gavage) for 5 days. O2- and peroxynitrite (ONOO-) production in Ao rings was determined by lucigenin and luminol chemiluminescence, respectively. Systolic blood pressure (SBP) was measured by the tail cuff method. EDR to acetylcholine in Ao rings (10-9to 10-5 M) was evaluated in organ baths. Ang II rats developed hypertension, Ao hypertrophy, and impaired EDR (both, maximal relaxation (Emax) and ED50). In Ang II rats, Ao O2- and ONOO- production was significantly increased. AML normalized SBP, Ao O2- and ONOO-production as well as EDR and Ao hypertrophy. Thus the in vivo vascular effects of Ang II which are linked to an increased O2- production are effectively blocked by Amlodipine. Clinically these studies suggest that in patients not achieving good blood pressure control with monotherapy, the combination of Amlodipine with agents that inhibit the renin angiotesnin system may have beneficial synergistic effects upon the blood pressure as well as the vasculature. (See Table) P < 0.05 vs Control and Ang II—AML; P < 0.05 vs Control. P < 0.05 vs Control and Ang II—AML; P < 0.05 vs Control.