Vitamin D-induced chronic hypercalcemia inhibits thick ascending limb NaCl reabsorption in vivo

Chronic hypercalcemia (HC) induced by dihydrotachysterol (DHT) is associated with a nephrogenic concentrating defect. The purpose of the present study is to assess the effects of HC on thick ascending limb (TAL) NaCl reabsorption in vivo by use of micro stop-flow technique. Feeding DHT (4.25 mg/kg diet) to rats was associated with an increase in plasma [Ca] within 24 h from 2.21 +/- 0.049 to 2.71 +/- 0.047 mM (P less than 0.001), which remained elevated during the 7-day period of study. Ambient plasma arginine vasopressin (AVP) in polydipsic HC rats was 3.10 +/- 0.605 pg/ml, a value not different from that measured in pair-fed control rats (1.82 +/- 0.260 pg/ml). A urine-concentrating defect developed after 3 days and occurred without nephrocalcinosis or reduced glomerular filtration rate (GFR). The estimated TAL [NaCl] after all stop-flow periods in HC rats did not decrease to the same extent as in controls. The rate constant of NaCl reabsorption derived from linear regression analysis of the ln[NaCl] vs. time for 0-15 s was significantly reduced by 25% in the HC nephrons. In addition, the minimum [NaCl] established after 30-60 s of contact time increased by 36% in HC nephrons. These data provide evidence that reduced TAL NaCl reabsorption, and not reduced GFR, nephrocalcinosis, or deficient AVP, contributes to the presence of a renal concentrating defect in DHT-induced chronic HC.