Effect of angiotensin II receptor blockade combined with a thiazide diuretic on plasma aldosterone escape in healthy subjects

Objective: The chronic administration of ARBs is associated with an incomplete ALDO suppression suggesting either a partial blockade of adrenal angiotensin AT1 receptors or a breakthrough phenomenon. We have investigated the adrenal response to exogenous Ang II in healthy subjects receiving an ARB alone or in association with a thiazide diuretic. Methods: Thirty subjects participated in this randomised, controlled, single-blind study. The effect of a 1 h infusion of Ang II (3 ng/kg/min) on plasma ALDO levels were investigated in each volunteer before and after a 1-week single-blind administration of either irbesartan 300 mg alone or in association with hydrochlorothiazide (HCTZ) 12.5 or 25 mg. After one week washout period, volunteers were switched to olmesartan 20mg/HCTZ 25 mg or valsartan 160/HCTZ 25 mg or losartan 100/HCTZ 25mg for another week. Results: Compared to pre-treatment values and to irbesartan alone, trough plasma ALDO values were higher in subjects receiving Irb300/12.5, and were significantly increased with Irb300/25 (to 4.9±1.8 and 7.5±1.2 ng/dl respectively, p<0.05). In participants receiving Olm20/25, Vals160/25 and Los100/25, trough ALDO were also significantly elevated. Before any treatment, exogenous Ang II increased plasma ALDO acutely from 3.6±0.7 to 13.2±1.3 ng/dl. With Irb300, the ALDO response to Ang II was blunted by 50-60% independently of the presence of HCTZ (p<0.05). The ALDO response to Ang II was also significantly blunted by about 50-60% with Olm20/25 and Vals160/25, but not with Los100/25. Conclusion: These results demonstrate that recommended doses of most ARBs only partially block the adrenal response to exogenous Ang II when associated with a thiazide diuretic. The ARB-thiazide association accentuates the aldosterone escape thus further justifying the use of mineralocorticoid antagonists in some clinical circumstances such as resistant hypertension or hypertension with severe end organ damage.