Angiotensin II receptor antagonist improves age-related endothelial dysfunction

Background. We previously demonstrated that the angiotensin converting enzyme (ACE) inhibitor, enalapril, prevents the age-related impairment of endothelium-dependent hyperpolarization and relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF). Objective. To test whether angiotensin II type 1 (AT₁) receptor antagonists would also improve age-related endothelial dysfunction. Methods. Normotensive Wistar-Kyoto (WKY) rats were treated for 3 months with either the AT₁ receptor antagonist, candesartan cilexetil (3.5 mg/kg per day; candesartan group), or the ACE inhibitor, enalapril (20 mg/kg per day; enalapril group), from 9 to 12 months of age. Untreated 12-month-old WKY rats (old group) served as controls (n = 7-12). Results. The two treatments decreased systolic blood pressure comparably. EDHF-mediated hyperpolarization in response to acetylcholine (ACh; 10^-5 mol/l) in the presence of norepinephrine in mesenteric arteries was improved in both the candesartan and enalapril groups to a similar extent compared with the old group (candesartan group, -24 ± 3 mV; enalapril group, -21 ± 2 mV; old group, -13 ± 2 mV). EDHF-mediated relaxation was similarly improved in the candesartan and enalapril groups (maximum relaxation: candesartan group, 70 ± 7%; enalapril group, 63 ± 8%; old group, 33 ± 9%). Hyperpolarization and relaxation responses to levcromakalim, an ATP-sensitive K⁺-channel opener, were similar in all groups. Conclusions. These findings suggest that the AT₁ receptor antagonist is as effective as the ACE inhibitor in improving the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats. Thus AT₁ receptor antagonists might serve as novel tools with which to prevent endothelial dysfunction associated with aging.