Effects of Acetazolamide on Proximal Tubule Cl, Na, and HCO3 Transport in Normal and Acidotic Dogs during Distal Blockade

Abstract

A B S T R A C T It has been suggested that the establishment of a tubular fluid to plasma chloride gradient in the late proximal tubule by the reabsorption of bicarbonate (and other anions) in the early proximal tubule is responsible for a significant part of sodium chloride and water reabsorption in the proximal tubule. In the present study the effects of acetazolamide on proximal tubule water and electrolyte excretion were examined in 6 normal dogs and 10 chronic ammonium chloride-loaded dogs during distal blockade produced by ethacrynic acid and chlorothiazide administration. During distal blockade control urine/plasma osmolality and urine/plasma sodium were close to unity in all experiments. Urine/plasma chloride and urine/plasma bicarbonate were 1.21+0.02 and 0.75+0.07 in normal and 1.24+0.01 and 0.04+0.01 in acidotic dogs, respectively. After the administration of acetazolamide (20 mg/kg i.v.), there was a significant increase in urine flow, absolute and fractional excretion of sodium, bicarbonate, and chloride in all animals. Associated with these effects, urine/plasma osmolality and urine/ plasma sodium remained unchanged but urine/plasma chloride decreased significantly to 1.15±0.01 in normal and to 1.19+0.01 in acidotic dogs. In acidotic dogs there was a significant correlation between the increase in bicarbonate, sodium, or chloride excretion after acetazolamide and the plasma bicarbonate level (range 6.8-12.5 meq/liter). These data demonstrate a significant effect of acetazolamide on bicarbonate, sodium, and chloride reabsorption in the proximal tubule even in the face of severe acidosis. Moreover, the data suggest that the decrease in chloride reabsorption (and accompanying sodium) after acetazolamide is related to the decrease in bicarbonate reabsorption and the associated decrease in the transtubular chloride gradient.

<i>In vivo </i>Demonstration of Renal Carbonic Anhydrase Activity in the Fetal Lamb

“…Contrary to previous observations in adult animals (5,9), no significant increase is found in fetal sodium and chloride excretion during carbonic anhydrase inhibition. Such a differ ence between fetal and adult responses to ace tazolamide may be explained on the basis that the immature kidney regulates sodium in a dif ferent way than the mature adult kidney (15,24), and that sodium lost in the proximal nephrons is reabsorbed more distally (15).…”

Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure

“…The finding that hypochloraemia was associated with the greatest risk in patients with higher levels of serum bicarbonate and in those receiving high doses of loop diuretics supports the hypothesis that total body chloride depletion via diuretics may be more important than dilutional hypochloraemia. Although extensive research in the area of tubular chloride handling in response to non‐loop diuretics has not been conducted, it has been reported that co‐administration of acetazolamide with loop diuretics can reduce chloride losses by ∼5% . Furthermore, a theoretical improvement in the urinary loss of chloride could be accomplished with adjuvant thiazide diuretics which do not directly cause excess chloride loss .…”

Intracellular cAMP signaling by soluble adenylyl cyclase

“…Importantly, equivalent results were obtained in kidney slices 113 , after intravenous cAMP infusion via the femoral vein 117 , and in isolated ICs 117 . Although direct effects of increased external pH and/or [HCO 3 − ] on these processes have not yet been demonstrated, chronic CA inhibition with acetazolamide, which increases HCO 3 − delivery to the DT 119,120 , did stimulate the apical microvilli elongation (as well as the number of A-type ICs) 119 . Interestingly, as in epididymal clear cells, AMPK activity opposes the role played by sAC-generated cAMP; it inhibits the VHA apical translocation and the development of microvilli in A-type ICs 113 .…”