Hypocalcemia is the main factor responsible for the genesis of secondary hyperparathyroidism in chronic renal disease. Studies with parathyroid cells obtained from uremic patients indicate that there is a shift in the set point for calcium-regulated hormone (parathyroid hormone [PIH) secretion. Studies were performed in dogs to further clarify this new potential mechanism. Hypocalcemia was prevented in uremic dogs by the administration of a high calcium diet. Initially, ionized calcium was 4.79±0.09 mg/dl and gradually increased up to 5.30±0.05 mg/dl. Despite a moderate increase in ionized calcium, immunoreactive PTH (iPTH) increased from 64±7.7 to 118±21 pg/ml. Serum 1,25(0H-)D3 decreased from 25.4±3.8 to 12.2±3.6 pg/ml. Further studies were performed in two other groups of dogs. One group received 150-200 ng and the second group 75-100 ng of 1,25(OH)2D3 twice daily. The levels of 1,25(OH)2D3 increased from 32.8±3.5 to a maximum of 69.6±4A pg/ml. In the second group the levels of serum 1,25(0H)D3 after nephrectomy remained normal during the study. Amino-terminal iPTH did not increase in either of the two groups treated with 1,25(OH)2D3.In summary, the dogs at no time developed hypocalcemia however, there was an 84% increase in iPTH levels, suggesting that hypocalcemia, per se, may not be the only factor responsible for the genesis of secondary hyperparathyroidism.

Recent studies have shown that oxidation of bovine PTH-(1-34) [bPTH-(1-34)] with H2O2 abolished the vascular effects of PTH in rats and dogs, but the hypercalcemic effect of the oxidized PTH was preserved in the Japanese quail in vivo. These observations seem at variance with previous studies from our laboratory in the isolated perfused canine tibia preparation in which no uptake of immunoreactive PTH or stimulation of cAMP release was demonstrated during infusion of oxidized bPTH-(1-34). The present studies examine the skeletal and renal effects of oxidized PTH-(1-34) in rats and dogs in vivo. Oxidation of PTH with H2O2 reduced its activation of adenylate cyclase by 95% in dog renal cortical membrane. Awake normal dogs were studied before and during the infusion of bPTH-(1-34) or oxidized PTH-(1-34) (4 U/kg X h). With active PTH, ionized Ca+2 rose in each dog (range, 0.7-1.5 mg/dl), while with oxidized PTH, Ca+2 remained within 0.1 mg/dl of the baseline values. Fractional excretion of PO4 rose from 1.58 +/- 0.6% to 29.5 +/- 2.5% with active PTH and from 1.4 +/- 0.4% to 5.7 +/- 1% with oxidized PTH. The latter did not differ from the value in vehicle-infused dogs. Further studies were performed in 30 acutely parathyroidectomized rats. Plasma Ca+2 rose from 8.2 +/- 0.1 to 9.0 +/- 0.3 mg/dl with active PTH (20 micrograms/kg), fell to 7.7 +/- 0.2 with oxidized PTH, and fell to 7.3 +/- 0.3 mg/dl with vehicle. In parathyroid-intact rats plasma Ca+2 increased by 0.9 mg/dl whether given active PTH, oxidized PTH, or vehicle. We conclude that oxidation of bPTH-(1-34) results in loss of both the renal and skeletal effects of PTH in vivo in rats and dogs.

Although it is well known that aluminum (Al) plays a role in the development of osteomalacia in patients with chronic renal failure, the mechanisms are not fully understood. Since the osteoblasts are the cells responsible for the formation of osteoid tissue, which is greatly affected in patients with Al-induced osteomalacia, it is possible that Al could affect the number of osteoblasts or interfere with their function. To further characterize this potential mechanism, we performed studies in isolated perfused tibiae from normal and Al-treated dogs. In this system, when PTH is added to the perfusate, cAMP, a major marker of osteoblasts, is released. The dogs were divided into two groups: control, and Al-treated (0.75 mg/kg, iv, 5 days a week for 3 months). Thereafter, the dogs were killed, and the tibiae were perfused in vitro. PTH-(1-34) (3-4 ng/ml) and 3-isobutyl-1-methylxanthine (an inhibitor of phosphodiesterase) were added to the perfusate. Basal cAMP secretion was the same in both groups of dogs. After PTH was added to the perfusate, cAMP increased to a peak of 188.2 +/- 30.6 pmol/min in the normal dogs vs. 113 +/- 8.15 in Al-treated dogs (P less than 0.05). Cumulative cAMP secretion over a 30-min period was 766 +/- 127.9 pmol in the normal dogs vs. 455.6 +/- 38.2 pmol in the experimental animals (P less than 0.05). The histological appearance of bone biopsies taken before and after Al administration are consistent with a suppressive effect of the cation on osteoblast function. In particular, the number of osteoblasts had decreased 8-fold (P less than 0.01) under the influence of Al, and tetracycline-based measurements of mineralization kinetics show that osteoblast-mediated calcification was dysfunctional (P less than 0.01-0.025). On the other hand, the histological features of the post Al treatment biopsies suggest that at some time during its administration, the cation stimulates osteoblastic activity. For example, new (woven) bone formation was present in two dogs, and in another, lamellar bone, deposited under the influence of Al, covered the entire trabecular surface. Moreover, Al-associated osteoid was deposited independent of prior resorptive activity, indicating that the cation promotes bone formation in the absence of prior resorption. In keeping with its trophic effect on matrix deposition, Al also led to extensive marrow fibrosis in five dogs, indicating that Al also stimulates the activity of fibroblasts, cells closely related to osteoblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypocalcemia in chronic renal failure (CRF) has been attributed in part to a skeletal resistance (S.R.) to the calcemic action of parathyroid hormone (PTH) as a consequence of low levels of 1,25(OH)2D3. To further elucidate the role of 1,25(OH)2D3 in the genesis of S.R., the calcemic effect of infusion of synthetic b-PTH 1-34 was examined in dogs before and after 7, 90 and 180 days of CRF. The maximum increment in ionized calcium after the infusion of PTH in the normal dogs was 1.15 +/- 0.13 mg/dl, decreased to 0.84 +/- 0.09 after 7 days, 0.68 +/- 0.1 after 90 days and to 0.66 +/- 0.11 mg/dl after 180 days of CRF. Thereafter, the dogs received 1,25(OH)2D3, 0.5 microgram daily for seven days and the studies were repeated. No improvement in the calcemic response to PTH was observed (0.57 +/- 0.26 mg/100 ml). Subsequently, a parathyroidectomy (PTX) was performed and 24 hours later the studies were repeated. After the infusion of PTH the calcemic response returned to normal (0.93 +/- 0.14 mg/dl). Further studies were performed in a group of four uremic dogs receiving no 1,25(OH)2D3, in which a PTX was performed 24 hours prior to the infusion of PTH. For this group, the increase in serum ionized calcium was 0.99 +/- 0.11 mg/dl. These values were not statistically different from normal dogs. In summary: (1) renal insufficiency was characterized by an abnormal calcemic response to PTH; (2) the administration of 1,25(OH)2D3 did not correct the S.R. to PTH; and (3) PTX performed 24 hours before the infusion of PTH restored the calcemic response to normal. These data suggest that high levels of endogenous parathyroid hormone desensitized the skeleton to the administration of exogenous PTH. These studies indicate that low values of 1,25(OH)2D3 are not directly responsible for the skeletal resistance to PTH in chronic renal failure.

During the development of cirrhosis ascites-edema, peripheral vasodilatation, hypotension and an increase of the plasma concentration of several neurohormones are frequently observed. Such complex changes in the hormonal profile hinders the assessment of the relative role of each in the pathophysiology of this disease. The purpose of this work was to evaluate in a rat model of experimental cirrhosis (phenobarbital/CCl4) the role of the renin-angiotensin system in the pre-ascitic stage of the disease using the converting enzyme inhibitor captopril. Cirrhotic rats showed diminished renal and hepatic perfusion. Compared to normal rats, glomerular filtration rate in cirrhotic rats was reduced from 0.75 +/- 0.11 to 0.42 +/- 0.06 mL/min/100 g BW, and renal plasma flow was reduced from 2.37 +/- 0.28 to 1.58 +/- 0.16 mL/min/100 g BW; the indocyanine green slope changed from -0.095 +/- 0.028 to -0.057 +/- 0.01; the plasma sodium concentration fell from 144 +/- 1.5 to 131 +/- 5.40 mEq/L (all < .05). The mean arterial pressure was not reduced in the cirrhotic rats. There was no ascites. Both the acute (25 mg i.v.) and chronic (25 mg i.p. daily plus 25 mg/L in drinking water) administration of captopril to cirrhotic rats induced an increase in glomerular filtration rate and renal plasma flow along with a steeper slope in indocyanine green decay (p < .05 for all three parameters) when compared to non-treated cirrhotic animals. No changes were observed in controls. In the balance studies, an increase in urinary volume along with a decrease in urinary osmolality was recorded in cirrhotic rats on chronic captopril treatment. In conclusion, our results show an activation of the renin-angiotensin system in these rats, as disclosed by the inhibition of the converting enzyme, as well as a possible interaction with ADH.