A Micropuncture Study of Proximal Tubular Function after Acute Hydrochlorothiazide Administration to Brattleboro Rats with Diabetes Insipidus

Abstract

1. Renal function in anaesthetized Brattleboro rats with hereditary hypothalamic diabetes insipidus was studied with micropuncture techniques before, and 1-3 h after, a single injection of hydrochlorothiazide.2. In rats given hydrochlorothiazide and kept in sodium and water balance, total glomerular filtration rate and superficial nephron filtration rate were similar to values in control animals, whereas fractional fluid reabsorption in the proximal tubule (as evidenced by tubular fluid/plasma inulin concentration ratios) was slightly, but significantly, reduced. This suggests that hydrochlorothiazide may have a small direct inhibitory effect on proximal tubular reabsorption.3. When rats were given hydrochlorothiazide and the resultant extra urinary sodium losses were not replaced, there was a marked antidiuresis. In these animals total glomerular filtration rate was reduced by 23% and superficial nephron filtration rate by 27% when compared with values in control rats. Fractional proximal tubular fluid reabsorption increased significantly whereas absolute proximal fluid reabsorption was unaffected.4. It is concluded that the reduction in body sodium which follows acute hydrochlorothiazide administration over-rides any inhibitory effect of the drug on proximal tubular reabsorption, and leads instead to an increase in fractional fluid reabsorption at this site. This effect, combined with the fall in glomerular filtration rate, results in a greatly reduced delivery of fluid to the more distal nephron segments, and is probably largely responsible for the observed antidiuresis.

Antidiuretic Effect of Hydrochlorothiazide in Lithium-Induced Nephrogenic Diabetes Insipidus Is Associated with Upregulation of Aquaporin-2, Na-Cl Co-transporter, and Epithelial Sodium Channel

“…Consistent with this notion, in a study on Brattleboro rats with central DI, Walter et al (34) showed that the antidiuresis that follows acute administration of HCTZ is entirely secondary to the natriuresis and consequent sodium depletion induced by the drug. However, Shirley et al (9) showed that the mechanism of sustained antidiuresis during chronic HCTZ administration in DI differs from that of the acute response.…”

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

“…and prepared surgically for micropuncture experiments as described in previous studies from this laboratory (Walter et al 1979, Shirley et al 1990. First, the animals were placed on a servocontrolled heated operating table to maintain the rectal temperature at 37 C. The right jugular vein was then cannulated, followed by a tracheotomy, cannulation of the right femoral artery, catherization of the bladder through a suprapubic incision and exposure of the left kidney via a flank incision.…”

Effect of frusemide on lithium clearance and proximal tubular reabsorption in anaesthetized rats.

“…The animals were anaesthetized with Inactin (120 mg kg-', I.P. ; Byk Gulden, Konstanz, Germany) and prepared surgically for micropuncture as described in previous reports from this laboratory (Walter, Laycock & Shirley, 1979;Shirley, Zewde & Walter, 1990). Sodium chloride solution (150 mmol 1-l), containing LiCl (9 mmol 1-1), was infused i.v.…”

“…After surgery, [3H]inulin (Amersham International, Aylesbury) was included in the infusion (80 ,uCi primer; 80,uCi h-'), and after a 90 min equilibration period all animals underwent a 90 min control period. During the control period the clearances of [3H]inulin and lithium were measured and at least three micropuncture collections were made from late surface convolutions of proximal tubules (Walter et al 1979).…”