Role of the loop segment in the urinary concentrating defect of hypercalcemia

Abstract

Hypercalcemia is associated with impaired urinary concentrating ability. To explore the mechanism(s) by which hypercalcemia impairs chloride transport in the loop of Henle, we carried out in vivo microperfusion of the loop segment in Sprague-Dawley rats rendered acutely hypercalcemic (12.1 +/- 0.1 mg/dliter) by calcium gluconate infusion. Control rats were infused with sodium gluconate and had normal plasma calcium (8.0 +/- 0.2 mg/dliter). Compared to control, fractional chloride reabsorption was decreased (61 +/- 4 to 50 +/- 3%; P less than 0.05) and early distal chloride increased 74 +/- 6 to 98 +/- 3 mEq/liter (P less than 0.001) in hypercalcemia. During hypercalcemia, infusion of verapamil failed to increase fractional chloride reabsorption (49 +/- 4%; P less than 0.05) or decrease early distal chloride (95 +/- 2; P less than 0.05) toward control values. Similarly, indomethacin did not improve fractional chloride reabsorption (48 +/- 4%; P less than 0.05) or distal chloride concentration (93 +/- 7; P less than 0.05). In control rats infused with Ringers HCO3, the addition of calcium 8.0 mEq/liter to the perfusate increased early distal calcium (9.22 to 3.11 mEq/liter) but was associated with no change in fractional chloride reabsorption (-6 +/- 6%) and a slight decrease in early distal chloride (-9 +/- 3 mEq/liter; P less than 0.05). These data are consistent with the hypothesis that an elevated plasma, not luminal calcium, concentration impairs chloride reabsorption in the loop segment, primarily the ADH-stimulated component. This may have an important role in the urinary concentrating defect of hypercalcemia.

Endogenous prostaglandin E2 mediates inhibition of rat thick ascending limb Cl reabsorption in chronic hypercalcemia.

“…This is in clear contrast to other loop segment studies where J. was 2 50% of the perfused rate (18,28 ( 14,20). Specificity offurosemide.…”

“…There is evidence from in vitro studies that acute increases in extracellular [Ca2+] can directly inhibit AVP stimulated production of cAMP and thus could mediate the transport defect ( 17 ). In acute hypercalcemia, loop Cl reabsorption is decreased by an indomethacin-resistant mechanism ( 18). However, two previous studies have shown that renal PGE2 excretion is strikingly elevated in rats with chronic hypercalcemia ( 15,19).…”

AQP3, p-AQP2, and AQP2 expression is reduced in polyuric rats with hypercalcemia: prevention by cAMP-PDE inhibitors

“…IT IS WELL KNOWN THAT HYPERCALCEMIA in both humans and experimental animals is associated with a urinary concentrating defect and significant polyuria (11,20,30). Despite considerable experimental work (2,3,10), the precise pathogenic mechanisms involved in the impaired urinary concentration remains only partly understood and it is likely to be multifactorial. Several lines of evidence have pointed to a significant defect in countercurrent multiplication in hypercalcemia, which is associated with decreased medullary hypertonicity (2,28,29) and to a defect in collecting duct water reabsorption.…”

Reduced expression of Na-K-2Cl cotransporter in medullary TAL in vitamin D-induced hypercalcemia in rats

“…Alterations in hormone levels, especially arginine vasopressin (AVP) release or response (4), renal hemodynamics (8), and renal tubular function (19) have been examined as possible mediators of the defect. However, the pathogenic mechanisms involved in the impaired urinary concentration are likely to be multifactorial.…”