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Published on: March 12, 2013
Macrolide-induced aldosterone suppression as a functional marker of KCNJ5-mutated aldosterone-producing adenoma: a
Gian Paolo Rossi1, Brasilina Caroccia1, Alessandro Bressan1
1Internal & Emergency Medicine and Hypertension Center, University of Padua, Padua 35128, Italy.
Objective:
Primary aldosteronism (PA), the most common curable form of hypertension, is frequently caused by aldosterone-producing adenomas (APAs) harbouring KCNJ5 mutations that render aldosterone synthesis sensitive to macrolides in vitro. This study aimed to evaluate whether a single dose of roxithromycin reduces plasma aldosterone concentration (PAC) and blood pressure (BP) in patients with KCNJ5-mutated APA, and to characterize the haemodynamic effects of macrolides in mice.
Design:
Prospective, within-patient pharmacologic challenge.
Methods:
At the specialized Hypertension Center, University of Padua, eligible consecutive hypertensive patients screened for PA underwent a pharmacologic challenge with a single oral dose of roxithromycin to investigate the within-patient changes in PAC, active renin, cortisol, and BP.
Results:
Among 373 challenged patients, 18 had KCNJ5 (G151R or L168R)-mutated APA, 25 had wild-type APA, and 307 had no PA. Roxithromycin reduced PAC (P < .001) only in APA with KCNJ5 mutation, albeit it did not lower BP values. However, it produced a small BP decrease in non-PA hypertensive patients. Mouse studies showed that this BP lowering can be due to macrolide-induced attenuation of angiotensin II actions involving enhancement of endothelium- and nitric oxide-dependent vasodilation.
Conclusions:
The selective suppression of aldosterone secretion with roxithromycin in KCNJ5-mutated APA in vivo, which aligns with ex vivo mechanistic data, can represent a functional marker of KCNJ5 mutations and could help guide precision subtyping of PA patients. Macrolides also exhibit an aldosterone-independent antihypertensive effect in non-PA patients, which involves nitric oxide-dependent vasodilation.
