22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. (41/62881)

BACKGROUND: Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. METHODS: Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. RESULTS: In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. CONCLUSIONS: These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease.  (+info)

Hemodialysis with high-calcium dialysate impairs cardiac relaxation. (42/62881)

BACKGROUND: During hemodialysis (HD), serum ionized calcium is directly related to the dialysate calcium concentration. We have recently shown an acute induction of hypercalcemia to impair left ventricular (LV) relaxation. In the current study we sought to establish whether changes in serum Ca++ also affect LV function during HD. METHODS: We echocardiographically examined the LV relaxation and systolic function of 12 patients with end-stage renal disease before and after three HD treatments with dialysate Ca++ concentrations of 1.25 mmol/liter (dCa++1.25), 1.5 mmol/liter (dCa++1.50), and 1.75 mmol/liter (dCa++1.75), respectively. Age- and sex-matched healthy controls were also examined echocardiographically. RESULTS: The LV posterior wall thickness and the interventricular septum thickness, and the LV end-diastolic dimension and the end-systolic dimensions were significantly greater in the patients when compared with the controls, and the LV fractional shortening, the ratio of peak early to peak late diastolic velocities (E/Amax), and the isovolumic relaxation time (IVRT) showed impairment of LV relaxation and systolic function in the patients. Serum ionized calcium increased significantly during the dCa++1.5 HD (1.24 +/- 0.10 vs. 1.34 +/- 0.06 mmol/liter, P = 0. 004) and dCa++1.75 HD (1.19 +/- 0.10 vs. 1.47 +/- 0.06 mmol/liter, P = 0.002), and plasma intact parathyroid hormone decreased significantly during the dCa++1.75 HD (medians 8.2 vs. 2.7 pmol/liter, P = 0.002). LV systolic function was not altered during any of the treatments. The changes in E/Amax and IVRT suggested impairment of relaxation during all sessions, but only during the dCa++1.75 HD was the impairment statistically significant (E/Amax 1. 153 +/- 0.437 vs. 0.943 +/- 0.352, P < 0.05; IVRT 147 +/- 29 vs. 175 +/- 50 msecond, P < 0.05). CONCLUSION: HD with high-calcium (dCa++1. 75 mmol/liter) dialysate impairs LV relaxation when compared with lower calcium dialysate (dCa++1.25 and dCa++1.5 mmol/liter) treatments.  (+info)

Biochemical indices of osteomalacia in pregnant Asian immigrants in Britain. (43/62881)

Serum calcium, phosphate and alkaline phosphatase, and urinary calcium excretion were examined during the second trimester of uncomplicated normal pregnancy in Asian immigrants to Britain and in local Caucasians. The mean serum calcium was significantly lower in Asians than in Caucasians, and the mean serum alkaline phosphatase was significantly higher in Asians. The geometric mean of the urinary calcium excretion was highly significantly lower in Asians than in Caucasians. The variances of the serum calcium, serum alkaline phosphatase, and urine calcium excretion did not differ significantly in the two populations. This indicates that there is a shift in values of immigrant Asians as a group compared with Caucasians. A comparison with figures obtained on normal nonpregnant persons of both suggests that the shift is not an inherent feature of the Asian population.  (+info)

Bombesin stimulates adhesion, spreading, lamellipodia formation, and proliferation in the human colon carcinoma Isreco1 cell line. (44/62881)

The neuropeptide bombesin and its mammalian homologue, gastrin-releasing peptide (GRP), enhance proliferation in some but not all human tumor cell lines. The pathophysiological relevance of the bombesin/GRP receptor (GRP-R), which is expressed in 30% of human colon tumor cell lines and in 24-40% of native tumors, has not been clearly assessed at this time. We studied the effects of bombesin in the recently characterized human colon carcinoma Isreco1 cell line. Competitive reverse transcription-PCR showed a high GRP-R mRNA level in Isreco1 cells, and binding studies confirmed the expression of bombesin/GRP-subtype receptors (Kd = 0.42 nM; Bmax = 18,000 sites/cell). Exposure to bombesin resulted in an increase of intracellular calcium concentrations. Bombesin (1 nM) induced cell spreading at 24 h (21.7+/-1.6% versus 6.4+/-0.8% in control cells; P<0.01) and markedly increased the formation of lamellipodia. In addition, adhesion of Isreco1 cells to collagen I-coated culture dishes was stimulated in the presence of 1 nM bombesin (69+/-6% versus 42+/-1% in control cells; P<0.01). Finally, bombesin significantly increased [3H]thymidine uptake by Isreco1 cells in a dose-dependent manner, with a first significant response at 0.1 nM and a maximal effect at 100 nM bombesin (192.2+/-9.7% of control). These results clearly indicate that bombesin exerts morphological, adhesive, and proliferative effects on Isreco1 cells, suggesting that expression of the bombesin/GRP-R may contribute to the malignant properties of colon carcinoma cells.  (+info)

Cell-specific peptide binding by human neutrophils. (45/62881)

Analysis of peptide binding to human neutrophils (PMN) using phage display techniques has revealed cell-specific motifs reactive with the PMN surface. Phage libraries displaying either linear 9-mer or cyclic 10-mer and 6-mer peptides were incubated with normal human neutrophils followed by elution of bound phage with low pH (pH 2.2) and non-ionic detergent. Three rounds of selection generated several related peptide sequences that bound with high avidity to PMN. Using the linear 9-mer library, PMN-binding phage expressed peptides with the motif (G/A)PNLTGRW. The binding of phage bearing this motif was highly specific since no binding was observed on lymphocytes, fibroblasts, epithelial, or endothelial cells. Functional assays revealed that phage bearing the sequence FGPNLTGRW induced a pertussis toxin-sensitive increase in PMN cytosolic calcium analogous to that observed with Galphai coupled receptors. Other prominent motifs identified included phage bearing the consensus DLXTSK(M/L)X(V/I/L), where X represents a non-conserved position. Phage with this motif bound exclusively to a sub population of human PMN that comprised approximately 50% of the total and did not elicit a calcium response. The binding of such phage to PMN was prevented by co-incubation with competing peptides displaying identical or similar sequences (IC50 range from 0.6 micromol/L to 50 micromol/L for DLXTSK and GPNLTG, respectively). We speculate that these techniques will be useful in identifying functional cell-specific binding motifs and contribute to the development of new therapeutic and diagnostic strategies in human disease.  (+info)

Active transport of calcium across the isolated midgut of Hyalophora cecropia. (46/62881)

1. The net flux of 45Ca from lumen to blood side across the isolated and short-circuited Cecropia midgut was 1-9 +/- 0-2 muequiv. cm-2h-1 in 8 mM Ca and the flux ratio was as high as 56 to 1. 2. The calcium influx was depressed by anoxia; 73% after 30 min. 3. The kinetics of Ca transport were anomalous; the apparent Km varied with Ca concentration from less than 0-2 to greater than 5-6 mM Ca and the apparent Vmax varied from less than 1-3 to greater than 3-3 muequiv. cm-2h-1. 4. The calcium influx showed a delay before the tracer steady state was attained, indicating the existence in the transport route of a calcium pool equivalent to 5-7 muequiv/g. wet weight of midgut tissue. 5 High calcium (16 mM) depressed the short-circuit current and potassium transport from blood to lumen side across the midgut. 6. Calcium depressed magnesium transport, from lumen to blood side across the midgut, and magnesium depressed the calcium transport. 7. Ca transport by the midgut does not regulate the Ca level in the haemolymph in vivo; it merely aids the diffusion of calcium down its electrochemical gradient. However, Ca transport may assist the uptake of the nutrients from the midgut contents.  (+info)

Interactions of membrane potential and cations in regulation of ciliary activity in Paramecium. (47/62881)

Ciliary activity in Paramecium was investigated in different external solutions using techniques of voltage clamp and high frequency cinematography. An increase in the external concentration of K, Ca or Mg ions decreased the resting potential. It had no effect on ciliary activity. When the membrane potential was fixed, an increase in external Ca or Mg and, to a lesser extent, an increase in K concentration, raised the frequency of normal beating or decreased the frequency of reversed beating of the cilia. Similar effects resulted from membrane hyperpolarization with constant ionic conditions. Increase in concentration of Ca, but not of Mg or K, enhanced hyperpolarization-induced augmentation of ciliary frequency. Increase in Ca concentration also specifically augmented the delayed increase in inward current during rapid hyperpolarizing clamp. The results support the view that [Ca]i regulates the frequency and direction of ciliary beating. It is suggested that the insensitivity of the ciliary motor system to elevations of the external concentrations of ions results from compensation of their effects on [Ca]i. Depolarization itself appears to increase [Ca]i while elevation of the external ion concentrations at a fixed membrane potential appears to decrease [Ca]i.  (+info)

Electrophysiological evidence for tetrodotoxin-resistant sodium channels in slowly conducting dural sensory fibers. (48/62881)

A tetrodotoxin (TTX)-resistant sodium channel was recently identified that is expressed only in small diameter neurons of peripheral sensory ganglia. The peripheral axons of sensory neurons appear to lack this channel, but its presence has not been investigated in peripheral nerve endings, the site of sensory transduction in vivo. We investigated the effect of TTX on mechanoresponsiveness in nerve endings of sensory neurons that innervate the intracranial dura. Because the degree of TTX resistance of axonal branches could potentially be affected by factors other than channel subtype, the neurons were also tested for sensitivity to lidocaine, which blocks both TTX-sensitive and TTX-resistant sodium channels. Single-unit activity was recorded from dural afferent neurons in the trigeminal ganglion of urethan-anesthetized rats. Response thresholds to mechanical stimulation of the dura were determined with von Frey monofilaments while exposing the dura to progressively increasing concentrations of TTX or lidocaine. Neurons with slowly conducting axons were relatively resistant to TTX. Application of 1 microM TTX produced complete suppression of mechanoresponsiveness in all (11/11) fast A-delta units [conduction velocity (c.v.) 5-18 m/s] but only 50% (5/10) of slow A-delta units (1.5 +info)