Abstract Body: Background. Somatic mutations in the KCNJ5 potassium channel involve up to 70% of the patients presenting with primary aldosteronism (PA) caused by an aldosterone-producing adenoma (APA). Macrolides corrected the altered function of the two common mutations G151R and L168R, in vitro suggesting their potential usefulness for personalized management of patients with KCNJ5-mutated APA. Hence, we investigated if the macrolide roxithromycin that restored the KCNJ5 channel function could lower plasma aldosterone and blood pressure (BP) in KCNJ5-mutated APA patients.
Methods and design. In a within-patient study we assessed changes of plasma aldosterone, active renin, cortisol and BP induced by an oral roxithromycin (150-300 mg) challenge, in consenting consecutive hypertensive patients. In parallel, we investigated the vascular and BP effects of macrolides ex vivo and in vivo in mice.
Results. We recruited 425 consecutive patients: 19 had G151R - or L168R - mutated APA, 27 KCNJ5 wild-type APA, and the rest had no identifiable cause of hypertension. Roxithromycin lowered the plasma aldosterone concentration (p<0.001), not BP, in the G151R- and L168R-mutated APA patients, but not in the wild-type. However, an aldosterone-independent BP decrease was seen in the much larger cohort of hypertensive patients without PA. In mice experiments, studies showed that this was accounted far by a significant anti-hypertensive effect of macrolides that involved an endothelium-NO-dependent vasodilatory action.
Conclusions. The roxithromycin-induced fall of plasma aldosterone concentration might be a marker of the presence of KCNJ5-mutated APA. Moreover, our studies unveiled an anti-hypertensive effect of macrolides that involves endothelium- and NO-dependent vasodilation.