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Tubular magnesium reabsorption was investigated by recollection micropuncture and in vivo microperfusion techniques in acutely thyroparathyroidectomized rats made magnesium deficient by dietary deprivation. Henle's loop which normally reclaims the major portion of filtered magnesium was examined by elevation of intraluminal magnesium concentration. The transport capacity in these conditions was significantly lower in magnesium deficient rats (41%) compared to normal animals (71%) at comparable magnesium delivery rates. Acute infusion of MgCl2 further depressed loop magnesium reabsorption independent of intraluminal magnesium delivery. Parathyroid hormone did not alter magnesium transport capacity in magnesium deficient rats but resulted in enhanced transport in acutely hypermagnesemic deficient rats. Calcium reabsorption followed a similar qualitative pattern as magnesium with respect to loop function and urinary excretion. These results are consistent with a depressed transport capacity for magnesium in the loop of Henle of magnesium deficient rats which is independent of intraluminal magnesium delivery and circulating parathyroid hormone level.

In renal failure, absolute calcium excretion is low, but fractional excretion (FE) of filtered load is increased. In order to determine the role of metabolic acidosis in contributing to increased FECa, we have studied thyroparathyroidectomized dogs in a control phase and following the induction of chronic renal failure, both during spontaneous metabolic acidosis and after correction with NaHCO3. FECa was 3.7% in controls and increased to 13.7% in azotemic acidotic dogs (p less than 0.01). After correction of acidosis FENa was not significantly changed, but FECa fell significantly, to 8.1% (p less than 0.01), while glomerular filtration rate, plasma calcium and filtered calcium load were unchanged. Thus although FECa is increased in nonacidotic azotemic dogs, acidosis further enhances calcium excretion by inhibiting renal tubular calcium reabsorption. These effects of metabolic acidosis may contribute to hypocalcemia and bone disease in azotemia.

Clearance and micropuncture studies have been performed in dogs to examine the effects of acute and chronic metabolic acidosis and acute alkalosis on tubular sodium and calcium transport. Acute metabolic acidosis, induced by the infusion of hydrochloric acid, decreased proximal fluid reabsorption and increased the fractional delivery of sodium and calcium to the distal tubule, but not to the final urine. In comparison with normal dogs, dogs with chronic metabolic acidosis (induced by feeding ammonium chloride) showed an increase in proximal fluid reabsorption and a dissociation of calcium from sodium reabsorption more distally, leading to an increased delivery of calcium relative to sodium at the distal tubule and in the final urine. The infusion of sodium bicarbonate to correct chronic metabolic acidosis, both in intact and thyroparathyroidectomized (TPTX) dogs, reduced proximal fluid reabsorption and caused a selective enhancement of calcium reabsorption relative to sodium in the more distal nephron, resulting in a reversal of the dissociation observed in acidosis, both at the distal tubule and in the final urine. By contrastin fusion of sodium chloride in parathyroid-intact acidotic dogs did not reduce proximal fluid reabsorption or enhance tubular calcium reabsorption. In nonacidotic dogs, both intact and TPTX, infusion of sodium bicarconate to induce acute alkalosis resulted in selhese data demonstrate the presence of a component of tubular calcium reabsorption situated beyond the proximal tubule, which is inhibited by chronic (but not acute) metabolic acidosis and enhanced by metabolic alkalosis (or bicarbonate infusion) independently of parathyroid hormone.

Magnesium and calcium transport was studied in the superficial proximal tubule, loop of Henle, and superficial distal tubule of the rat by in vivo microperfusion. Magnesium chloride was used to vary plasma and perfusate magnesium concentration. Perfusion with magnesium-free Ringer solution resulted in little magnesium entry into the tubule lumen in either normomagnesemic or hypermagnesemic rats. Magnesium concentration increased with water abstraction along the perfused proximal tubule whether markedly above or below plasma concentrations. Absolute proximal magnesium reabsorption increased with perfusate concentration; however, fractional magnesium and calcium reabsorption decreased in proportion to net sodium reabsorption with elevated extracellular magnesium. Magnesium absorption increased in the loop of Henle proportional to luminal magnesium concentration. Sodium and calcium reabsorption was not affected. Acute elevation of plasma magnesium, however, significantly depressed absolute magnesium reabsorption to a greater degree than calcium whereas sodium was unchanged. The effects of extracellular magnesium onloop reabsorption were reflected in the final urine. Reabsorption of sodium, calcium, and magnesium in the perfused distal tubule was concentration-dependent and not altered by luminal or extracellular magnesium concentration.

Because the rat papilla has parathyroid hormone (PTH)-sensitive adenylate cyclase and because of indirect evidence that PTH may alter collecting duct water and also calcium transport, the effects of PTH on rat papillary collecting duct water and calcium transport have been studied. PTH in concentrations of 50 and 500 ng/ml significantly increased diffusional water permeability by 20 and 38%, respectively, while 5,000 ng/ml had no additional effect. This permeability response was small when compared to a 78% increase in water permeability with a maximal (0.5 ng/ml) concentration of antidiuretic hormone (ADH). The normal increase in water permeability with ADH was depressed in the presence of PTH (500 ng/ml) but was overcome when the ADH concentration was increased from 0.5 to 5 ng/ml. Neither PTH nor ADH altered the permeability of the collecting duct to calcium which was low (0.19 +/- 0.03 micron/s). Increasing either the bath or perfusate calcium concentration from 1 to 5 mM did not alter calcium permeability. These studies suggest that PTH acts as a partial agonist to ADH within the papillary collecting duct and that PTH is unlikely to have a major role in collecting duct calcium transport.

Recollection micropuncture and clearance studies were performed on 21 thyroparathyroidectomized hamsters to characterize the effect of chlorothiazide on tubular sodium, calcium, and magnesium transport. Acute administration of chlorothiazide resulted in a marked natriuresis while urinary calcium excretion fell and magnesium remained unchanged. The fraction of sodium, calcium, and magnesium remaining at the late proximal tubule increased modestly from 65 +/- 4 to 75 +/- 3, 68 +/- 3 to 75 +/- 4, and 78 +/- 4 to 85 +/- 2%, respectively. Distal tubular fluid to ultrafilterable plasma (TF/UF) sodium concentration rose from 0.24 +/- 0.03 to 0.44 +/- 0.04 whereas distal TF/UFCa concentration fell from 0.58 +/- 0.05 to 0.38 +/- 0.06. The fraction of sodium remaining at the distal tubule rose from 4.0 +/- 1.4 to 10.0 +/- 1.4% while that of calcium decreased from 10.2 +/- 1.1 to 7.6 +/- 1.2% following administration of chlorothiazide. No change was observed in distal delivery of magnesium. Thus chlorothiazide acted in the distal tubule to decrease sodium reabsorption, enhance calcium transport, and had little effect on distal magnesium reabsorption. These data are consistent with the distal tubular action of chlorothiazide which is independent of parathyroid hormone.

Micropuncture experiments were performed in thyroparathyroidectomized dogs to examine the influence of changes in filtered calcium load on segmental tubular calcium reabsorption. Filtered calcium load was changed either by reducing glomerular filtration rate (GFR) by aortic clamping (group I) or by progressive calcium infusion (group II) to increase plasma ultrafilterable calcium concentration (UFCa). The results suggest that fractional proximal calcium reabsorption responds similarly to altered filtered load, whether produced by changes in GFR or UFCa. In contrast, fractional reabsorption by the loop segment is progressively reduced as UFCa is increased but is relatively unchanged by alterations in filtered load secondary to altered GFR. These data indicate a specific parathyroid hormone-independent reciprocal effect of UFCa on calcium reabsorption in the loop segment, which may be an important determinant of urinary calcium excretion.

In vitro microperfusion experiments were performed on the cortical proximal straight tubule of the rabbit to examine the effect of acid base disturbances on calcium and magnesium transport by this segment of the nephron. During acidosis (pH 7.22 +/- 0.01) net calcium reabsorption was reduced, whereas during alkalosis (pH 7.82 +/- 0.02) net calcium reabsorption was increased. Our flux experiments with 45Ca indicate that the efflux of Ca from the lumen to the bath remained the same during acidosis; however, the back-flux (bath to lumen) of calcium increased. On the other hand, during alkalosis the efflux of calcium rose and the influx of calcium remained unchanged. These changes in fluxes during acid-base disturbances can be accounted for mainly by changes in ionized calcium as a result of pH changes. We failed to observe any effect of acid-base changes on net magnesium transport by the superficial proximal straight tubule.

1. The effect of purified bovine parathyroid hormone on renal tubular reabsorption of sodium and calcium has been studied by micropuncture in intact and recently thyroparathyroidectomized dogs. 2. Parathyroid hormone increased the rejection of sodium and calcium proportionately at the late proximal tubule in both intact and operated dogs. 3. In both groups of dogs, there was increased delivery of sodium and calcium to the distal tubule after the hormone. However, the Ca/Na ratio decreased, suggesting some selective enhancement of calcium reabsorption before the superficial distal puncture site. 4. In the final urine, the Ca/Na ratio decreased highly significantly in both groups of dogs, indicating a further selective effect of parathyroid hormone on calcium reabsorption in or beyond the distal convoluted tubule.

Recollection of micropuncture experiments were performed on acutely thyroparathyroidectomized rats rendered magnesium deficient by dietary deprivation. Urinary magnesium excretion fell from a control of 15 to 3% of the filtered load after magnesium restriction. The loop of Henle, presumably the thick ascending limb, was the major modulator for renal magnesium homeostasis. The transport capacity for magnesium, however, was less in deficient rats than control animals. Absolute magnesium reabsorption increased with acute infusions of magnesium chloride but was always less in magnesium-deficient rats than control rats for any given filtered load, which suggests either a defect of a resetting of the reabsorption mechanism. Recollection micropuncture demonstrated that this was a characteristic of the loop of Henle. Proximal magnesium reabsorption remained unchanged at 15% of the filtered load and was unaffected by magnesium deficiency or acute magnesium repletion. Distal tubular magnesium reabsorption was limited during depletion and increased to a similar extent in control and deficient rats with enhanced magnesium delivery. Calcium reabsorption was not altered in magnesium deficiency; however, elevations of extracellular magnesium resulted in a specific inhibition of calcium reabsorption within the loop of Henle. These data suggest that overall control of renal magnesium reabsorption occurs within the loop of Henle and that the proximal tubule reabsorbs a constant fraction of the filtered load despite variations in body magnesium status.

The tubular reabsorption of calcium has been studied in chronic metabolic alkalosis and acidosis. Clearance studies were performed in five conscious mongrel dogs during control periods and during alkalosis and acidosis both before and after thyroparathyroidectomy. After thyroparathyroidectomy, normocalcemia was maintained with oral dihydrotachysterol, and thyroxine was replaced. An initial control study was followed by the induction of chronic metabolic alkalosis by repeated gastric drainage for 4 days through a previously implanted gastric fistula. A second control study 1 week after alkalosis was followed by the induction of acidosis by feeding ammonium chloride, 10 gm daily for 3 days. A final control study was performed 1 week later. Serum proteins, GFR, and filtered calcium load were not significantly different in control, alkalosis, or acidosis. Alkalosis, in both intact and TPTX dogs, was associated with no change in TRNa in comparison with controls (94.6% vs. 95.4 in intact, p greater than 0.05; 95.0% vs. 96.3% in TPTX, p greater than 0.05). By contrast, TRCa increased significantly (97.2% vs. 95.5, p less than 0.05 in intact; 98.0% vs. 95.0, p less than 0.05 in TPTX). In acidosis, TRNa in both intact and TPTX dogs was unchanged in comparison with control (96.4%, p greater than 0.05 and 96.6%, p greater than 0.05, respectively), and TRCa was significantly decreased (to 91.9%, p less than 0.01 and 83.3%, p less than 0.001, respectively). These data indicate that chronic metabolic alkalosis increases the TRCa independently of changes in TRNa, filtered calcium load, or parathyroid activity.

A close relationship has been observed between the clearance rates of sodium and calcium under a variety of diuretic conditions. The thiazide diuretics act differently in dissociating the renal tubular reabsorption of sodium and calcium. This phenomenon has been further investigated using recollection micropuncture and clearance techniques in a group of 14 dogs subjected to three consecutive experimental phases: expansion to 3% of body weight (BWt) with Ringer's solution, chlorothiazide infusion at 20 mg/kg/h, and furosemide in a prime of 10 mg/kg/ and a 10 mg/kg/h infusion. Diuretic losses were balanced with infusion of equal volumes of Ringer's solution throughout the experiment. Chlorothiazide increased the fractional excretion (FE) of sodium almost threefold while FE(Ca) was not significantly altered. Furosemide increased FE(Na) and FE(Ca) to an approximately equal, and more marked, degree. This dissociation of sodium and calcium reabsorption after chlorothiazide was also evident in the superficial distal tubule, where (tubule fluid/plasma sodium) (TF/P(Na)) increased from 0.32 to 0.49 (P < 0.01) and TF/(ultrafiltrate)UF(Ca) was unchanged (0.35-0.31). Furosemide markedly reduced the transtubular concentration gradient for both sodium (0.86) and calcium (0.94). TF/P(Inul in) decreased progressively from 3.79 to 2.78 to 2.33 in three phases. In the late proximal tubule, chlorothiazide induced a fall of TF/P(Inul in) from 1.57 to 1.44 (P < 0.01), but the ratio TF/UF(Ca): TF/P(Na) was unchanged. Furosemide had no significant proximal effect. It is concluded that acute administration of chlorothiazide reduces sodium reabsorption in the distal hephron, presumably the cortical diluting segment, without affecting calcium reabsorption.