Effects of Calcium - Modulating Hormones on Thiazide Receptor ty ’ 2

Thiazide diuretic drugs act in the distal convoluted tubule (DCI) to inhibit a Na Cl cotransporter and enhance reabsorption of luminal calcium. The density of receptors for thiazides in the rat DCI is known to be increased by adrenocortical steroids, furosemide, and bendroflumethiazide, but decreased by ischemia. Because the DCI is a physiologic site of action by calcitonin and parathyrold hormone, this study examined the effects of these calcitropic hormones in thyroparathyroidectomized Sprague-Dawley rats on ( 1) the density of the rat thiazide receptor (1ZR), as quantitated by binding of (3H)metolazone to renal membranes, and (2) urinary electrolyte excretion rate. Salmon calcitonin (sCT) (20 to 100 ng/h) (1) increased the density of the renal 1ZR twofold, an effect that is maximal by 6 h after sCT administration, and (2) decreased urinary calcium excretion rate. Adequate dietary calcium must be provided for the effects of sCT to be observed. Regression analysis demonstrated that renal 1ZR density correlated negatively with total urinary calcium excretion rate but not with plasma calcium ion concentration. In addition, neither rat calcitonin (rCT), at doses that cause hypocalcemla, nor parathyrold hormone, at doses that cause hypercalcemia, produce direct effects on TZR density in the DCI of the thyroparathyroidectomized rat. Our findings indicate that upregulation of IZR by sCT, which occurs independently of plasma calciumion concentration, is likely via a calcitonin-like receptor other than that for rat calcitonin itself. T he distal nephron, comprised of the distal convoluted tubule (DCT), the connecting tubule and the collecting duct, plays a key role in the net total body balance of calcium. Specifically, the DCT reabsorbs 8 to 10% of the ifitered load of calcium ( 1). This reabsorption occurs against a chemical and electrical gradient ( 1 ). Physiological regulation of tubular calcium reabsorption occurs in the DCT and/or connecting tubule segments and can be dissociated from Na reabsorption with amilonide and thiazide diuretic drugs or after hormonal modification by parathyroid hormone (PTH) ( 1-3). Thiazide diuretics are an important class of drugs that inhibit an apical Na Cl symporter and at the same time enhance calcium reabsorption (4). Rat thiazide drug receptors can be quantitated by the ability of renal membranes to bind [3H]metola.zone, a potent diuretic with a thiazide-like mechanism of action (5). These receptors have been shown to be under regulation. Furosemide (6), bendroflumethiazide (7) and adrenocortical steroid (8,9) administration increase TZR density whereas only 10 min of ischemia results in decreased [3Hlmetolazone binding (10). Parathyroid hormone (PTH) and calcitonin (CT) act to regulate the amount of calcium in the urine at the level of the DCT in most species. The major renal effects of PTH in the rat are phosphaturia and increased renal calcium reabsorption ( 1 1 ). The effects of CT on urinary calcium excretion rate have been ambiguous with reports of increased ( 1 2) and decreased ( 13, 14) calcium excretion rate. Recent studies suggest that CT increases calcium reabsorption ( 15, 16). In the rat, these effects of CT have been elicited by using salmon CT (sCT), human CT, or porcine CT. However, there are no reports in the literature showing an effect of administered rat CT (rCT) on renal excretion of calcium in the rat. In this paper, we examine the effect of rat and salmon CT and rat PTH on the (1 ) density of the TZR, by quantifying the maximal binding of[3H]metolazone to renal membranes, and (2) urinary electrolyte excretion in thyroparathyroidectomized (TPTX) Sprague-