Nicardipine and hydrochlorothiazide in essential hypertension.

Nicardipine is an investigational dihydropyridine calcium channel blocking agent. One hundred fifty-one patients with hypertension received either 30 mg nicardipine t.i.d. or 25 mg hydrochlorothiazide b.i.d. in a double-blind, randomized, multicenter trial. After 4 weeks of therapy and at the end of the dosing interval, nicardipine reduced arterial pressure by 10/6 mm Hg and 12/6 mm Hg in the supine and standing positions, respectively (all p less than 0.01). In the hydrochlorothiazide group, the reductions were 12/6 mm Hg and 14/6 mm Hg, respectively (all p less than 0.01). The maximum reduction in blood pressure of 16/14 mm Hg supine and 20/15 mm Hg standing occurred within 1 hour after administration of nicardipine. The mean reduction in the hydrochlorothiazide group after 1 hour was 14/11 mm Hg supine and 16/12 mm Hg standing. Neither drug affected autonomic reflexes associated with maximum exercise. Nicardipine increased urinary sodium excretion during the 4-hour period after the first dose. Adverse effects of nicardipine were primarily extensions of its vasodilator effect and included flushing, headache, and edema.

Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro. These effects were compared with those of human parathyroid hormone (1-34), hPTH (1-34). Equal doses of PTH-rP(1-34) and hPTH(1-34) produced equivalent stimulation of adenylate cyclase in vitro in bone cells and kidney cells and tubules. Subcutaneous injection of PTH-rP(1-34) in mice caused a significant dose-related increase in blood ionized calcium similar to that seen with hPTH(1-34) at equivalent doses. Repeated injections of equal doses of both peptides caused sustained hypercalcemia which was significantly greater in PTH-rP(1-34)-treated mice, although each induced comparable increases in histomorphometric indices of osteoclastic bone resorption. PTH-rP(1-34) and hPTH(1-34) also caused similar increases in bone resorption when incubated with fetal rat long bones in organ culture. Infusion of either peptide into thyroparathyroidectomized rats suppressed urinary calcium excretion and increased urinary excretion of cyclic AMP. PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis.

Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins.

Hypercalcemia is frequently observed in patients with multiple myeloma and renal failure. Whether Bence Jones protein (BJP) is directly nephrotoxic and how and whether hypercalcemia might contribute to this putative nephrotoxicity is currently unclear. To examine this issue, we studied the effect of modest hypercalcemia on the glomerular filtration rate (GFR) of rats exposed to a BJP that by itself had been found to be nonnephrotoxic. Three groups of rats were studied. All were anesthetized and underwent a baseline measurement of inulin clearance (Cin). After this, group 1 (n = 13) rats were given 2 ml of vehicle (phosphate-buffered saline solution [PBS]) and were then made hypercalcemic with an infusion containing 0.048 mol/L CaCl2. At the end of 2 hours a second Cin was measured. Group 2 rats (n = 8) were given 100 mg BJP in 2 ml PBS and a non-calcium-containing infusate. Group 3 (n = 11) rats were given 100 mg of the BJP in 2 ml PBS and then the calcium-containing infusate used in group 1 rats. Rats in groups 2 and 3 also had a second Cin measured at the end of 2 hours. Renal blood flow was measured with an electromagnetic flow probe. At the completion of the second clearance, kidneys were processed for renal histologic assessment. The serum calcium level measured during the second Cin period was 13.5 mg/dl for group 1, 7.9 mg/dl for group 2, and 13.7 mg/dl for group 3. No significant decrement in GFR was observed in group 1 or 2 rats. In contrast, group 3 rats had a 46% fall in GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of chronic administration of different Bence Jones proteins on rat kidney.

The role of Bence Jones proteins (BJPs) in the genesis of the renal dysfunction that develops in patients with multiple myeloma is not clearly defined. We previously evaluated renal function and morphology in a unique strain of rats (LOU/m) bearing tumors which synthesized BJPs with isoelectric points of 5.2, 4.3 and 6.7. Myeloma cast nephropathy developed in one tumor bearing group (pI 5.2), tubular necrosis was observed in another (pI 4.3), and renal function and histology remained normal in a third group (pI 6.7). To see if these renal outcomes were a function of the BJP being excreted or other factors which could be present in the tumor bearing animals, we have examined the effect of chronic intravenous administration of these three BJPs on renal function and histology in non-tumor-bearing LOU/m rats. Urine containing the BJP was collected from tumor bearing rats, sterilized by passage through a 0.2 mu millipore filter, concentrated to 50 mg/ml, and dialyzed extensively so as to remove material with a molecular weight less than 3500. Chronic indwelling-venous catheters were placed in non-tumor-bearing LOU/m rats and these rats were given 100 mg/day for five days of one of the three BJPs. Polyfructosan clearance (Cin) was measured prior to and following the five days of BJP administration. Renal histology was examined at the completion of the second Cin. In the pI 5.2 group (N = 6), a severe distal nephron cast nephropathy occurred and Cin fell from 2.88 +/- 0.24 to 0.90 +/- 0.17 ml/min (P less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Myeloma kidney cast nephropathy in a rat model of multiple myeloma.

Renal insufficiency occurs in some, but not all, patients with multiple myeloma and Bence Jones proteinuria. Many of these patients are found to have a distinctive renal lesion characterized by distal nephron cast formation. It has been proposed that the specific Bence Jones protein (BJP) which is produced by a myeloma tumor may play an important role in the genesis of this cast nephropathy and that patients excreting BJPs with the highest isoelectric points (pI) are those most likely to develop this cast nephropathy. We have utilized a rat model of multiple myeloma to further evaluate the relationship between Bence Jones proteinuria and the development of myeloma cast nephropathy. This model employed immunoglobulin-secreting tumors obtained from a unique strain of rats in which they spontaneously develop. These tumors were transplanted to a homologous strain of rats and the effect on renal function and morphology in these rats were evaluated. Four different kappa light chain synthesizing tumors were studied. Following transplantation of the tumors, all rats were maintained on a diet designed to produce an acid urine (pH 5.5 to 6.0) and maximal urinary concentration (2000 to 3000 mOsm/kg). Among the rats excreting BJP of pI 6.7, 17 of 18 had virtually normal renal histology. Of the 15 rats with BJP of pI 7.6, 11 also had normal renal histology. However, 12 of 12 rats excreting BJP of pI 5.2 developed a distal nephron, light chain containing cast nephropathy. In the pI 4.3 group, 6 of 12 rats developed acute tubular necrosis, and the remaining six animals sustained a less severe lesion which was characterized by the presence of bland hyaline casts. The mean serum creatinine level obtained at the time of sacrifice was elevated (compared to that found in sham-operated controls) in the pI 5.2 group (P less than 0.001) and the pI 4.3 group (P less than 0.01) but not in the pI 6.7 or 7.6 groups. These results do not support the concept that cationic BJP's are more nephrotoxic than those that carry a more negative charge and indicate that other factors must determine the nephrotoxicity of a given BJP.