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Mechanism of antidiuresis caused by bendroflumethiazide in conscious rats with diabetes insipidus
Author(s) -
Grønbeck Lene,
Marples David,
Nielsen Søren,
Christensen Sten
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701653
Subject(s) - endocrinology , medicine , diabetes insipidus , mechanism (biology) , antidiuretic , vasopressin , philosophy , epistemology
The mechanism underlying the antidiuretic effect of thiazide diuretics in diabetes insipidus (DI) is unknown. This study addressed two specific questions: is the reduction in urine flow rate ( V ) related to a decrease in the delivery of fluid from the pars recta of the proximal tubules (‘distal delivery’), and are there any changes in the expression and/or intracellular distribution of vasopressin stimulated water channels (AQP2) in the collecting ducts, during chronic thiazide‐induced antidiuresis? Nine Brattleboro rats with vasopressin‐deficient DI were treated for 5 days with bendroflumethiazide (BFTZ), 9 mg kg −1 day −1 orally, and 9 Brattleboro rats were left untreated. BFTZ‐treated DI rats showed a fall in V from ∼200 to ∼75 ml day −1 and an increase in urine osmolality from ∼130 to ∼400 mosmol kg −1 . BFTZ‐induced antidiuresis was associated with a persistent loss of sodium, but not of potassium. After 5 days of treatment, clearance studies in conscious rats showed a tendency towards decreases in effective renal plasma flow (−7%), GFR (−12%) and lithium clearance ( C Li ; used as marker for distal delivery) (−25%), compared with untreated controls, but none of these changes were statistically significant. There was no apparent relationship between C Li and V in BFTZ‐treated or untreated DI rats. BFTZ treatment did not change the expression of AQP2 in homogenates of cortex, outer or inner medulla from DI rats, or from normal Long Evans rats. Light and electron microscopic immunocyto‐chemistry revealed no changes in intracellular distribution of AQP2 in principal cells from inner medullary collecting ducts of BFTZ‐treated DI rats. We concluded, (i) that although the antidiuretic effect of BFTZ in rats with DI is associated with a net loss of Na, the decrease in V shows no association with changes in distal delivery, as estimated by C Li . (ii) Antidiuretic treatment with BFTZ does not alter the expression of subcellular distribution of AQP2 water channels in the collecting ducts. The mechanism underlying the chronic antidiuresis caused by thiazide diuretics in DI remains elusive.British Journal of Pharmacology (1998) 123 , 737–745; doi: 10.1038/sj.bjp.0701653