Author(s): Nawar Dalila [*] aff1 , Jürgen Brockmöller aff1 , Mladen Vassilev Tzvetkov aff1 , Markus Schirmer aff1 , Martin Haubrock aff2 , Stefan Viktor Vormfelde aff1
antihypertensive agents; aldosterone; hydrochlorothiazide; LHX4; loop diuretics; mineralocorticoid receptor; NR3C2 ; pharmacogenetics; polymorphisms; triamterene
Diuretic drugs control salt, water excretion and blood pressure and are one of most important drugs in hypertension and heart failure [1-4 ]. Rare genetic variants and frequent polymorphisms in the sodium-potassium-dichloride cotransporter (NKCC2), the sodium-chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) have been reported to affect electrolyte excretion when diuretics were applied [ 5 ]. The mineralocorticoid receptor (MR, aldosterone receptor) plays an important role in sodium reabsorption and potassium excretion and is partially mediated by transcriptional regulation of ENaC. Although less investigated, modulation of the renal outer medullary potassium channel (ROMK) by MR has also been suggested [6 ]. Twelve polymorphisms in the MR gene, NR3C2 , have been implicated with in vivo phenotypes (Table 1). The Ile180Val polymorphism (rs5522) has been especially implicated with neuropsychiatric phenotypes [7-9 ], but diuretic drug effects have been poorly investigated in relation to these 12 polymorphisms given in Table 1.
Here we investigated, whether NR3C2 polymorphisms are implicated in urinary electrolyte excretion in two single-dose crossover studies: One with 96 volunteers on bumetanide, furosemide and torsemide, and one in 107 volunteers, on hydrochlorothiazide, triamterene and moderate sodium chloride restriction.
Patients & methods
We investigated the urinary electrolyte excretion in two single-dose crossover studies in healthy, male Caucasian volunteers [5,22 ]. The first study was on the loop diuretics bumetanide, furosemide and torsemide. The second study was on two doses of hydrochlorothiazide, on triamterene and on moderate sodium chloride restriction. The two study populations were unrelated to each other. Both studies were single-blind, three-arm, triple-crossover studies randomized in the order of drug application. Both studies were approved by the ethics committee of the University Medicine Göttingen. All volunteers provided written informed consent before they were included in the studies. To avoid hypovolemia, the subjects were repeatedly encouraged to drink water or theophylline-free and caffeine-free tea in both studies.
The first study consisted of three periods separated by at least 2 weeks. Each period had a run-in day and a drug day. The subjects were asked to adhere to a NaCl-restricted diet from 48 h prior to drug administration until 24 h after drug intake. Subjects were advised how to restrict NaCl intake. On the drug days, the participants took single oral doses of 2 mg bumetanide, 80 mg furosemide and 10 mg torsemide. Blood and urine were collected in intervals over 24 h after drug intake. In this study, 95 Caucasian men completed the bumetanide period, 93 the furosemide period and 92 the torsemide period. The participants were on average 28 years old (mean, range 19-50 years), weighed 78 kg (57-93 kg) and were 182 cm tall (170-198 cm).
The second study also consisted of three periods separated by at least seven days. Each period consisted of three days: a run-in day, a moderate...