Reduced hyperpolarization of endothelial cells following high dietary Na+: effects of enalapril and tempol

High dietary Na+ is associated with impaired vascular endothelial function. However, the underlying mechanisms are not completely understood. In the present study, we investigated whether the endothelial hyperpolarization response to acetylcholine (ACh) exhibited any abnormalities in Wistar rats fed a high-salt diet (HSD) for 1month and, if so, whether chronic treatment with the angiotensin-converting enzyme inhibitor enalapril or the anti-oxidant tempol could normalize the response. Membrane potential was recorded using the perforated patch-clamp technique on the endothelium of rat aorta. Acetylcholine (2 mu mol/L) produced a hyperpolarization sensitive to TRAM-34, a blocker of intermediate-conductance Ca2+-sensitive K+ channels (IKCa), but not to apamin, a blocker of small-conductance Ca2+-sensitive K+ channels (SKCa). NS309 (3 mu mol/L), an activator of SKCa and IKCa channels, produced a hyperpolarization of similar magnitude as ACh. In the HSD group, the ACh-evoked hyperpolarization was significantly attenuated compared with that in the control group, which was fed normal chow rather than an HSD. Similarly, the hyperpolarization produced by NS309 was weaker in tissues from HSD-fed rats. Combination of HSD with chronic enalapril treatment (20mg/kg per day for 1month) normalized endothelial hyperpolarizing responses to ACh. Chronic tempol treatment (1mmol/L in tap water for 1month) prevented the reduced hyperpolarization to ACh. The results of the present study indicate that excess in dietary Na+ results in a failure of endothelial cells to generate normal IKCa channel-mediated hyperpolarizing responses. Our observations implicate oxidative stress mediated by increased angiotensin II signalling as a mechanism underlying altered endothelial hyperpolarization during dietary salt loading.