Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line.

Acute parathyroid hormone exposure induces vascular smooth muscle relaxation. In contrast, continuous infusion of parathyroid hormone leads to vasoconstriction and an elevation of blood pressure. Despite the known effects of parathyroid hormone on vascular smooth muscle, possible direct effects on the vascular endothelium have not previously been investigated. Using a human umbilical vein endothelial cell line, we found that parathyroid hormone increased both intracellular calcium and cellular cAMP content in these endothelial cells. Furthermore, exposure of these cells to increasing concentrations of parathyroid hormone stimulated both [(3)H]thymidine incorporation and endothelin-1 secretion. Parathyroid hormone/parathyroid hormone-related peptide receptor mRNA could be detected at low levels in these cells. In summary, these data demonstrate that endothelium-derived cells contain functional parathyroid hormone receptors. The potential physiological role of these receptors remains to be determined.

Expression of inducible nitric oxide synthase in breast cancer correlates with metastatic disease.

Breast cancer is characterized by its ability to metastasize rapidly. Factors that might facilitate this metastatic potential include tumor vascularity. Nitric oxide (NO), a labile compound synthesized by NO synthase (NOS), is a major regulator not only of physiologic vascular tone but also of the abnormal vascularity associated with many tumors. To test whether NOS is expressed in primary breast tumors and whether its expression is associated with the presence of metastasis, we analyzed the expression of the inducible NOS in 22 primary breast tumors, and to investigate its association to other gene products related to the metastatic ability of tumor cells, we correlated the expression of the inducible NOS with the expression of the nm23 protein (the product of the putative antimetastatic gene nm23). We found a very strong correlation between the presence of NOS and axillary lymph node metastasis and between NOS and the absence of nm23 protein. These data suggest that NO synthesis and the resulting increase in blood flow to the tumor play a role in the facilitation of tumor metastasis.

Novel effect of insulin: insulin-stimulated Na+ transport is mediated by hydrolysis of phosphoinositides.

Previous studies showed that insulin stimulation of electrogenic Na+ transport in renal epithelial cells is mediated by a calcium-dependent signal transduction mechanism. The present study was performed to determine whether the insulin-induced increase in intracellular Ca2+ (Cai2+) was mediated by hydrolysis of phosphatidylinositol and release of inositol trisphosphate. Experiments were conducted with cultured A6 cells, derived from Xenopus Laevis, grown on permeable supports. Addition of insulin resulted in 2 to 3 fold increases in inositol trisphosphate and a 50% increase in 1,2 diacylglycerol within 10s, which corresponded to the time-course, previously reported, of insulin stimulated increases in Na+ transport and Cai2+. Further studies showed that aldosterone, previously shown to stimulate an increase in 1,4,5-inositol trisphosphate at onset of the rise in Na+ transport, also increased DAG levels during the initial phase of stimulation of Na+ transport. These studies provide the first evidence that a biological response induced by insulin is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) which results in two products, inositol trisphosphate which causes the release of Ca2+ from intracellular stores and 1,2 diacylglycerol. In addition this study provides further support for the proposal that a common signal transduction mechanism mediates electrogenic Na+ transport by multiple agonists.

Parathyroid hormone stimulates electrogenic sodium transport in A6 cells.

The effects of parathyroid hormone (PTH) on sodium homeostasis in the distal tubule are not well defined. Using A6 cells as a model for distal tubular epithelium we measured equivalent short circuit current (leq), as an estimate of net sodium transport. We found that PTH increased leq in a dose-dependent manner. DDA, an agent which inhibits adenylate cyclase, decreased PTH-activated sodium transport, suggesting a role for cAMP elevation in PTH effects. Moreover, addition of Rp-cAMP, an inhibitor of cAMP-dependent protein kinase, partially blocked the PTH-stimulated leq. PTH also elicited a sustained increase in [Ca2+]i in A6 cells. This elevation in [Ca2+]i was abolished by removal of calcium from the extracellular medium, suggesting the involvement of calcium influx pathways. In fact, addition of the calcium channel blocker nitrendipine to PTH-stimulated leq partially blocked PTH-activated sodium transport. Taken together these data demonstrate that PTH stimulates electrogenic sodium transport in A6 cells and that this effect may be mediated through a rise in both intracellular calcium and cellular cAMP.

Mechanism of insulin-stimulated electrogenic sodium transport.

Studies were performed to determine the signal transduction mechanism involved in the onset of insulin stimulated electrogenic sodium transport (Ieq) in cultured A6 cells. Insulin stimulated Ieq at a threshold concentration of one nM and a half-maximum concentration of approximately 3 nM. The onset of action occurred within 10 seconds and the increase in Ieq was augmented by pretreatment with aldosterone, similar to the action of vasopressin. Insulin stimulated an increase in Ca2+i in a dose-dependent manner that involved release from intracellular stores. Hormone stimulated Ieq was dependent on increases in Ca2+i because pretreatment with 5, 5' dimethyl BAPTA/AM blocked the increase in sodium transport. Further studies with dihydroxyclorpromazine, trifluoperazine and genistein, inhibitors of PKC, Ca2+i dependent, calmodulin dependent kinases and tyrosine kinase, respectively, suggested that the action of insulin was dependent on activation of these kinases. In contrast, insulin stimulated Ieq was independent of changes in cAMP, because insulin did not increase the accumulation of cAMP, and inhibition of adenylate cyclase with 2', 5' dideoxyadenosine did not affect transport. These results suggest that insulin, as previously shown for aldosterone, activates apical membrane amiloride sensitive sodium channels by a calcium-dependent second messenger system.

[Erythrocyte levels of ALA-dehydrase and uro-synthetase in chronic renal insufficiency (author's transl)]. / Estudio de los niveles eritrocitarios de ala-dehidrasa y uro-sintetasa en la insuficiencia renal crónica.

Erythrocyte levels of ala-dehydrase and uro-synthetase as well as hematocrit, hemoglobin, iron levels and serum iron binding capacity were studied in a group of 28 patients with chronic renal failure in hemodialysis and compared to those of a control group. As is usual, hematocrit, hemoglobin an iron levels were significantly decreased, as were ala-dehydrase levels, while uro-synthetase levels were within normal levels. These results are interpreted as a blockade of the biosynthetic pathway of the protoporphyrins, which lends support to the hypothesis of an existing defect in hemoglobin synthesis in patients with chronic renal failure.

[Threshold for bicarbonate in epileptic children in treatment with anticonvulsant drugs (author's transl)]. / Descenso del umbral renal para el bicarbonato en niños tratados con anticonvulsivantes.

The study comprised 31 ambulatory epileptic children aged 1,5-14 years (mean: 7.37), receiving treatment with anticonvulsant drugs. Authors found that renal threshold for bicarbonate was inferior when compared to control group (mean = 21.3 mEq/l., SD = 1.75; mean = 25.34 mEq/l., SD = 1.29; p less than 0.0001), low calcemia (mean = 9.12 mg./dl., SD = 0.51; mean = 9.43, SD = 0.45; p less than 0.01) and elevated alkaline phosphatase (mean = 212.6 mU/ml., SD = 75.9; mean = 127.4, SD = 50.2; p less than 0.01). No significant difference in urinary excretion of cyclic AMP, phosphate or calcium was observed. Nineteen patients who had subnormal threshold (inferior to -2 SD in the control group) when compared with control group, had: low calcemia (p less than 0.01), high alkaline phosphatase (p less than 0.0001) and a similar urinary cyclic AMP, calciuria and phosphaturia. A negative correlation between renal threshold to bicarbonate and serum phosphate (r = -0.49, p less than 0.01) and a negative correlation between the urinary cyclic AMP and the duration of treatment (r = -0.42, p less than 0.05) was found. It is commented that although in deficiency rickets, proximal tubular acidosis is due to secondary hyperparathyroidism, in their patients despite they had biochemical characteristics of rickets, low calcemia and elevated alkaline phosphatase, the descent of renal threshold to bicarbonate is a nonparathoromone mediated phenomenon.

[A study of the urinary acidifying capacity of patients chronically treated with anticonvulsants (author's transl)]. / Estudio de la capacidad de acidificación de la orina en enfermos con ingestón crónica de anticonvulsivantes.

The subjects of this study were 18 patients with essential or secondary epilepsy under treatment with anticonvulsant drugs (hydantoins and phenobarbital) for periods of time varying between 8 months and 22 years. In all of them the serum levels of calcium, phosphorus, alkaline phosphatase, and the renal tubular capacity to acidify the urine were measured. Mean serum calcium and phosphorus levels were normal, while alkaline phosphatase was significantly elevated (p less than 0.0005). The renal threshold for bicarbonate was lowered to a mean of 23.01 +/- 2.86 (p less than 0.01). Distal tubular function was normal in all cases. When the patients are divided into two groups according to the duration of treatment (more or less than 100 months), the group with longest therapy shows an elevation of alkaline phosphatase (p less than 0.0005), a lowering of serum calcium (p less than 0.025) and a reduction of the renal threshold for bicarbonate (p less than 0.005) when compared to the group with shortest therapy.

[New enzymatic and endocrinological aspects in two cases of Werner's syndrome (author's transl)]. / Nuevos aspectos enzimáticos y endocrinológicos en dos casos de síndrome de Werner.

Results of endocrinological studies and of the investigation of intraerythrocytic glycolytic pathway carried out in two patients with Werner's syndrome are presented. An increase of glyceraldehyde 3-phosphate and 3-phospho-glycerokinase has been observed, but the significance of these original findings is still unknown. An hyperinsulinism after oral glucose overload has been demonstrated too. This finding, which has been reported by other authors, probably reflects a peripheral resistance to insulin action. Other endocrinological abnormalities were a decrease in the T3:T4 quotient and a slight delay in the FSH-LH peak to LH-RH.

[Renal tubular acidification in patients treated with anticonvulsants (author's transl)]. / Acidificación tubular renal en sujetos tratados con anticonvulsivantes.

Proximal and distal renal tubular acidification function has been studied in ten epileptics treated with phenobarbital and hydantoins. Plasma concentration of 25 OH D3 and urinary excretion of adenosine 3':5'-cyclic phosphate (cAMP) were also determined. Serum parathormone (PTH) was analyzed in five patients. Four of these ten patients showed a decreasing threshold for bicarbonates, suggesting a disturbance of the proximal tubular acidification function. These patients did not show diminishing plasma levels of 25 OH D3, and according to the results of cAMP and PTH determinations a hyperparathyroidism could be ruled out. Anticonvulsants lead to a disturbance of the renal acidification which is not derived from alterations of the phosphocalcic metabolism.

[Study of the acidification capacity of the urine in polyclonal hypergammaglobulinemia (author's transl)]. / Estudio de la capacidad de acidificación de la orina en las hipergammaglobulinemias policionales.

The renal capacity of acidification of urine was studied in 21 patients with hypergammaglobulinemia (polyclonal gammapathies) secondary to several conditions. The reabsorption threshold of bicarbonate was determined by Rodriguez-Soriano's technique; the acid and ammonium production was measured using Wrong and Davies' technique. Values for the bicarbonate threshold ranged from 18.5 to 29 mmol/liter of plasma bicarbonate with a mean value of 25 +/- 2.29; they were not significantly different from the control values. Urinary pH ranged from 4.6 to 5.8; ammonium excretion ranged from 18.4 to 114.5 microEq/min (mean value 63.01 +/- 25.36). Acidity values ranged from 13 to 65.05 microEq/min (mean value 33.61 +/- 19.36). Thhre was no statistical difference between these values and those obtained from the controls. We found no evidence that the acidification function of urine was limited in patients with hypergammaglobulinemia secondary to several conditions as compared with normal subjects. In the two cases in which this function was altered there was no reason why it should be attributed to hypergammaglobulinemia.

Pharmacokinetics of cephacetrile in patients undergoing haemodialysis.

The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were: a = 5.03 h-1, beta = 0.458 h-1, K12 = 2.337 h-1, K21 = 1.996 h-1 K13 = 1.154 h-1, Vc = 5.5081, Vp = 6.4481, Vdss = 11.9561. As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.

Metabolism of red blood cells in chronic renal failure. I. Glycolytic enzyme levels.

This paper starts a series on red blood cell (RBC) metabolism in patients with chronic renal failure (CRF). The glycolytic enzyme levels and in vitro half-lives of these patients' RBCs were determined. A number of enzymes (hexokinase, glucose-6-phosphate isomerase, fructose-6-phosphate kinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase) showed higher activities than in normal control RBCs. Other enzyme activities were normal. These results were discussed and several possible mechanisms considered. We favour the point of view of a shortened life span of the RBCs in CRF, making the most unstable enzymes of the glycolytic sequence appear increase as compared with normal controls.