Body Fluid Expansion in Acromegaly Is Related to Enhanced Epithelial Sodium Channel (ENaC) Activity

Abstract

Soft-tissue swelling and increased extracellular volume, two features of acromegaly, are related to the antinatriuretic effects of excess GH/IGF-I, but the precise pathophysiological mechanism is unclear. Our objective was to determine the effect of the GH excess on renal and extrarenal epithelial sodium channel (ENaC) activity. We conducted a prospective randomized open-label blinded-endpoint (PROBE) crossover study (www.ClinicalTrials.gov Identifier: NCT00531908) at a tertiary referral medical center and clinical investigation center. Sixteen patients (five females, 11 males) with acromegaly were randomly assigned to receive 20 mg amiloride (an ENaC blocker) and 25 mg furosemide (a Na-K-2Cl cotransporter blocker) under a high-sodium diet to suppress endogenous renin and aldosterone. Diuretic-induced changes in the urinary Na/K ratio (reflecting coupling between ENaC-mediated Na reabsorption and distal K secretion) and the intranasal amiloride-sensitive potential (reflecting extrarenal ENaC activity) were measured before and 6 months after (range, 1-12 months) treatment of acromegaly. Serum IGF-I concentrations normalized in all the patients after treatment of acromegaly. Baseline plasma renin and aldosterone concentrations remained unchanged after treatment. Active acromegaly, compared with controlled disease, was associated with an enhanced response [median (interquartile range)] to amiloride [urinary Na/K, 13.9 (9.8-19.5) vs. 6.3 (4.3-8.4) mmol/mmol, P = 0.0003], a reduced response to furosemide [urinary Na/K, 5.2 (4.6-7.2) vs. 7.1 (5.4-8.8) mmol/mmol, P =0.0151], and an increased intranasal amiloride-sensitive potential [5.8 (11.9-3.8) vs. 4.2 (6.4-2.1) mV, P = 0.031], respectively. GH/IGF-I excess in humans is associated with enhanced renal and extrarenal ENaC activity that may contribute to soft-tissue swelling and volume expansion in acromegaly.