Urinary excretion of aquaporin-2 after furosemide and felodipine in healthy humans.
OBJECTIVE
Furosemide inhibits renal sodium and chloride reabsorption in the loop of Henle. A compensatory increased reabsorption of sodium and water takes place in the collecting duct. It is not known whether aquaporin-2 (AQP2) renal water channels are involved in this compensatory reabsorption. In animals, dihydropyridine derivatives of calcium channel blockers down-regulate AQP2 in the collecting duct, but the effect has not been studied in humans. We sought to test the hypotheses that urinary excretion of aquaporin-2 (U-AQP2) increases after a single intravenous dose of furosemide, and that U-AQP2 decreases after a single oral dose of felodipine.


METHODS
In two randomized, single-blind, placebo-controlled, cross-over studies, we measured the effect of furosemide and felodipine on U-AQP2, urine volume, free water clearance (CH2O), and fractional excretion of sodium (FENa) in 13 healthy subjects in each study. Plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (ang II), aldosterone (aldo), atrial (ANP), and brain natriuretic peptides (BNP) were measured during the study. Glomerular filtration rate (GFR) was measured by constant infusion technique. U-AQP2 and hormones were determined by radioimmunoassay.


RESULTS
Furosemide treatment increased U-AQP2 (202%), urine volume (214%), and FENa by a factor of 11, (p < 0.001 for all), whereas CH2O and GFR were unchanged. After treatment with placebo, no differences were seen. Furosemide treatment increased AVP (18%), PRC (60%), ang II (100%), and aldo (98%) (p < 0.032); ANP was decreased by 29% (p < 0.001), whereas there was no change in BNP. The hormones were unchanged after placebo except for a minor decrease in ANP after placebo. Felodipine tended to increase U-AQP2, to decrease CH2O and urine volume and GFR, and to increase FENa, but the effect was not significantly different from placebo. Felodipine increased PRC (82%) (p < 0.003) and ang II, but decreased aldo, and increased AVP. After placebo, PRC was unchanged, whereas ang II, aldo and AVP were changed as after felodipine.


CONCLUSIONS
Furosemide treatment increased U-AQP2, AVP, and the activity of the renin-angiotensin-aldosterone system. These changes are most likely compensatory phenomena, which prevent an excess loss of sodium and water. Felodipine tended to increase U-AQP2.
Starklint
J
J
Department of Medical Research, Holstebro Hospital, Denmark. j.starklint@dadlnet.dk
Bech
J Nørgaard
JN
Pedersen
E Bjerregaard
EB
D000328:Adult; D000368:Aged; D051399:Aquaporin 2; D020346:Aquaporins / Q000652:urine*; D001835:Body Weight / Q000187:drug effects; D015736:Felodipine / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005665:Furosemide / Q000378:metabolism / Q000494:pharmacology*; D006262:Health; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry / Q000187:drug effects
C496023:AQP2 protein, human; D051399:Aquaporin 2; D020346:Aquaporins; D005665:Furosemide; D015736:Felodipine