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SUMMARY 1. The oral administration of polysodium metaphosphate in the rat causes an increase in the incidence of the scattered foci of calcification found in the kidneys of a small proportion of normal animals. 2. No abnormal calcification occurred in other tissues. 3. Mortality was not increased. 4. Growth was not affected. 5. Fertility, pregnancy, and lactation appear to be unaffected. 6. The determination of the dosage which gives the maximum suppression of urinary calculus formation for the minimum increase in renal parenchymal calcification is discussed. We wish to thank Professor L. N. Pyrah and Professor M. F. A. Woodruff for providing facilities for these experiments in their laboratories at Leeds University and Edinburgh University respectively, the Secretary of State for Scotland for the grant of financial assistance, and Messrs Albright & Wilson Ltd. for the supplies of polysodium metaphosphate. [ABSTRACT FROM AUTHOR]

SUMMARY 1. The theoretical basis of the use of orally administered polysodium metaphosphate to suppress stone formation in the urinary tract is discussed. 2. It is shown that the addition of polysodium metaphosphate to urine in vitro can prevent calcium oxalate precipitation. 3. A method of estimating the amount of polysodium metaphosphate excreted in the urine is described. 4. The stone-suppressing action of oral polysodium metaphosphate in rats is confirmed. 5. This action appears to be independent of changes in the pH or dilution of the urine. [ABSTRACT FROM AUTHOR]

SUMMARY A case of polycystic kidneys is described for which an auxiliary kidney in the form of an isolated loop of ileum was prepared. Irrigation of this loop usually resulted in clinical improvement, and the investigations carried out suggest that this was brought about by the removal of some toxic metabolite, possibly nitrogenous in character. [ABSTRACT FROM AUTHOR]

Summary The mammalian fetus is maintained hypercalcaemic relative to its mother primarily by the action of a placental calcium pump located in the basal plasma membrane of the trophoblast. It is suggested that the activity of this pump is stimulated by a mid-molecular fragment of parathyroid hormone-related protein [PTHrP(38-94NH [ABSTRACT FROM AUTHOR]

The motility of the reticulo-rumen has been measured in trained, conscious sheep using inflated balloons temporarily introduced to selected regions of that forestomach. The frequency and amplitude of the contractions of the reticulum and both the A and B waves of contraction of the rumen were measured under the same conditions before, during and after the administration of an i.v. bolus of either parathyroid hormone (PTH(1-34)) or PTH-related protein (PTHrP(1-34)) followed by its i.v. infusion. These two peptides are known to share a common receptor in other organs, e.g. the kidney. In this study they both showed an inhibitory effect on reticulo-ruminal motility. The effect of PTHrP(1-34) on the rate of ruminal blood flow was also examined and a significant reduction observed, after a transient increase. The secretion of endogenous PTH(1-34) was stimulated by a 32% reduction in the plasma calcium ion concentration induced by an i.v. infusion of sodium citrate. Associated with this were significant reductions in reticulo-ruminal motility, e.g. the reduction in the mean amplitude of the reticular contractions reflected the reduction in plasma calcium ion concentration. When the PTH(1-34)/PTHrP(1-34) receptor was blocked with [Asn10,Leu11,D-Trp12]PTHrP(7-34) before and during the induction of hypocalcaemia, all but one of the parameters of reticulo-ruminal motility were normalized. Indeed, by the day following the administration of this blocking agent, all these parameters had returned to their normal range. It is concluded that stimulation of the PTH(1-34)/PTHrP(1-34) receptor in reticulo-ruminal smooth muscle reduces the motility of this tissue and may play a role in the depression of motility of the digestive tract which is characteristic of clinical milk fever in the dairy cow.

Parathyroid hormone-related protein (PTHrP(1-34)) was infused into five sheep, each fitted with a large rumen cannula. After infusion, significant increases were observed in the total and ionized calcium concentrations in plasma but not in saliva. In contrast, significant decreases in the plasma concentrations of phosphate and potassium and corresponding increases in their salivary concentrations and clearance rates were observed. The salivary concentration of endogenous PTH1P(1-34) was significantly greater than that in plasma sampled simultaneously, but during the infusion of PTHrP(1-34) both plasma and salivary concentrations of PTHrP(1-34) increased.

The concentrations of plasma parathyroid hormone-like bioactivity and parathyroid hormone-related protein (1-86) (PTHrP) immunoreactivity were both higher in fetal pigs than in their mothers during the last 3 weeks of gestation. Both activities changed inversely with alterations in the plasma ionized calcium concentration. The data suggest that PTHrP may have a role in calcium homeostasis in the fetal pig, similar to its postulated role in sheep in the stimulation of calcium transport across the placenta.

Not only parathyroid hormone (PTH) but also parathyroid hormone-related protein (PTHrP) may play a role in calcium and phosphate homeostasis in ruminants. In five trained sheep, each with a large rumen cannula, the isolated rumen wash technique was used to measure electrolyte absorption rates from the rumen. After two control periods of measurement, 20 micrograms PTH(1-34) (n = 4), or PTHrP(1-34) (n = 5), was injected intravenously as a loading dose, followed by an infusion of 0.67 micrograms min-1 over 2 h. Both PTH(1-34) and PTHrP(1-34) significantly increased the absorption rates of calcium and phosphate from the reticulo-rumen. The increases in the absorption rates of magnesium, sodium and potassium observed were not significant. The same technique was also used to demonstrate that increasing the intraruminal calcium concentration from 1 to 4 mmol l(-1) caused corresponding increases in the net rate of absorption of both calcium and inorganic phosphate from the reticulo-rumen. Rumen epithelium was taken from four sheep and mounted in Ussing chambers so that fluxes of calcium could be measured in both directions using 45Ca. It was found that the addition of 100 ng ml-1 PTH(1-34) or PTHrP(1-34) to the serosal side increased the net calcium flux rates across the ruminal epithelium. It is concluded that both PTH and PTHrP can influence calcium and phosphate homeostasis in sheep not only by their recognized actions on bone and kidney but also on the absorption of these ions from the forestomachs.

Synthetic parathyroid hormone fragment PTH(1-34) has been reported recently to inhibit uterine contractions stimulated by a variety of agonists. We have studied the effect in this system of the parathyroid hormone-related protein fragment PTHrP(1-34) which shows 60% homology with PTH over the first thirteen amino acid residues. The effects of two different PTHrP fragments on acetylcholine-stimulated uterine contractions in vitro were studied. Whereas synthetic hPTHrP(75-86 amide) (10(-9)-10(-7) M) was without effect, synthetic hPTHrP(1-34) (10(-9)-10(-7) M) was capable of inhibiting, in a dose-related fashion, uterine muscle contractions precontracted with 10(-6) M-acetylcholine. In a second series of experiments the bovine PTH(3-34) fragment itself was shown to have no stimulatory effect on acetylcholine-stimulated contractions. Also this fragment in an equimolar concentration (10(-7) M) failed to antagonize the effects of PTHrP(1-34) on acetylcholine-stimulated uterine contractions. However, a 100-fold excess molar concentration of bPTH(3-34) (10(-6) M) completely abolished the inhibitory action of hPTHrP(1-34) (10(-8) M) on acetylcholine-stimulated uterine contractions. These results clearly show that the inhibitory action of PTH(1-34) and PTHrP(1-34) on uterine contractions depends on the integrity of the amino-terminal region of the molecule.

The fetal plasma magnesium concentration exceeds that of the mother but the difference is small compared to that of ionized calcium concentration. Although not fully independent of changes in maternal magnesaemia, fetal magnesaemia showed a high degree of autonomy during both hypermagnesaemic and hypomagnesaemic changes induced in the ewe. As with calcium, the placental gradient is reversed after fetal thyroparathyroidectomy (TXPTX) with thyroxine replacement. During perfusion in situ of the placenta from such TXPTX fetuses isolated from the fetus itself, a stable positive placental gradient of magnesium concentration could be re-established between the perfusing blood and the maternal circulation. As with calcium, this gradient could be increased by fetal calf parathyroid extract, parathyroid hormone-related protein (PTHrP 1-141), PTHrP (1-84) but not by PTHrP (1-34). It was concluded that a mid-molecule portion of PTHrP can stimulate a putative placental pump which is responsible for the gradients of both calcium ions and magnesium across the ovine placenta.

Perfusion in situ of the placenta of intact or previously parathyroidectomized fetal lambs has been used to assess the ability of three mid-molecule fragments of the human parathyroid hormone-related protein (PTHrP) molecule to stimulate the placental transport of calcium and magnesium. PTHrP(67-86 amide) was most effective but some activity was also shown by PTHrP(75-86 amide) and by PTHrP (75-84) in decreasing order. This placental action of PTHrP(67-86 amide) was rapid and could be observed using the placenta from an intact fetus, whereas it was necessary to use the placenta from a previously parathyroidectomized fetus to demonstrate stimulation of placental calcium transport by PTHrP(1-84). PTHrP(67-86 amide) may resemble the molecule that activates the placental calcium pump.

An assay for plasma osteocalcin (BGP) in ruminants is described. Satisfactory cross-reaction was obtained for bovine BGP in several species, namely ovine, cervine, caprine and human. Sample stability at room temperature, after freezing and thawing and after lyophilization and reconstitution is described. Sheep of both sexes have been used throughout and no significant sex effect has been noted. A series of experiments showed a lack of circadian rhythm of plasma BGP concentration in sheep. Plasma BGP values from sheep ranging in age from 0.25 to 7 years fell exponentially from 300 ng/ml at 0.25 years to approximately 50 ng/ml at 1.25 years of age where it remained until the end of the study at 7 years. Long-term administration of adrenocorticotrophic hormone (ACTH) depressed plasma BGP concentrations, although plasma BGP levels were not affected sufficiently by short-term administration of ACTH to increase plasma cortisol concentrations 10-fold during a period of 4 h. It was confirmed that dietary phosphate deficiency depressed plasma BPG concentrations. It is concluded that neither circadian variation nor the short-term stress of handling and bleeding untrained animals need be considered in sampling sheep for measurement of plasma BGP concentration and that the change with age reflected the pattern of development of skeletal maturity in sheep. Values in both growing and mature sheep were at least 6 times higher than in human subjects, which may reflect the 10-fold higher skeletal growth rate in sheep than in humans. This high skeletal activity in sheep may have been selected for in the development of highly productive breeds.