Amlodipine increased endothelial nitric oxide and decreased nitroxidative stress disproportionately to blood pressure changes

Abstract

Background:Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO-) and blood pressure (BP).Methods:Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO- release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method.Results:As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157±11nM to 55±6nM and increased ONOO- from 69±7nM to 156±19nM. The NO/ONOO- ratio, a comprehensive measurement of eNOS function, decreased from 2.3±0.3 to 0.3±0.1. Compared with vehicle, amlodipine treatment restored NO to 101±3nM, decreased ONOO- to 50±4nM, and increased the NO/ONOO- ratio to 2.0±0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149±3mm Hg (baseline) to 174±1mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167±3mm Hg vs. vehicle treatment.Conclusions:Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials. © 2013 American Journal of Hypertension, Ltd.