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PubMed1993

Calcium-binding proteins in the chick Edinger Westphal nucleus.

It has been suggested that the calcium-binding proteins, parvalbumin and calbindin-D28K, are involved in the control of intracellular calcium levels but their exact functions are unknown. Immunoreactivity for parvalbumin has been associated with rapidly firing cells, while calbindin has been implicated in protecting neurons from excitotoxicity. Since the chick Edinger Westphal nucleus contains two populations of neurons with different firing patterns, parvalbumin and calbindin immunoreactivities were examined in the Edinger Westphal nuclei of posthatch chicks to determine whether a particular subpopulation of neurons is associated with either protein. Moderate levels of parvalbumin immunoreactivity were found consistently associated with repetitively firing neurons in the lateral Edinger Westphal nucleus. In contrast, medial neurons expressed much lower levels of parvalbumin immunoreactivity. Many medial neurons were negative for parvalbumin although occasionally a few medial neurons stained as strongly as lateral neurons. Definitive calbindin immunoreactivity was absent from Edinger Westphal nuclei despite robust staining of cells in other parts of the brainstem and in control sections of cerebellum.

Action Potentials↗
PubMed1990

Morphological and chemical identification of neurons that project from the colon to the inferior mesenteric ganglia in the guinea-pig.

Labelled nerve cells were located in the distal colon of the guinea-pig 4-5 days after the retrograde tracing agent, Fast blue, was injected into the inferior mesenteric ganglia. Labelled neurons were only found in the myenteric plexus. Their frequency increased from oral to anal and was greater towards the mesenteric border, compared with the anti-mesenteric aspect, of the colon. Many retrogradely labelled neurons were immunoreactive for vasoactive intestinal peptide or calbindin. In the inferior mesenteric ganglia, vasoactive intestinal peptide and calbindin immunoreactive nerve fibres surrounded the same clumps of nerve cell bodies. Almost all calbindin and vasoactive intestinal peptide immunoreactive terminals degenerated after the nerves running from the large intestine to the inferior mesenteric ganglia were cut. It is concluded that the great majority of calbindin and vasoactive intestinal peptide immunoreactive terminals in the inferior mesenteric ganglia arise from nerve cell bodies in the myenteric plexus of the large intestine.

Amidines↗
PubMed1996

Differential distribution of calcium-binding proteins in the dorsal column nuclei of rats: a combined immunohistochemical and retrograde tract tracing study.

This study aimed to investigate whether different calcium-binding proteins are present in morphologically and functionally separate cell groups in the dorsal column nuclei of rats. Thalamic-projecting neurons were identified by iontophoretic injection of an intraaxonal tracer substance, choleragenoid, into the ventroposterolateral thalamic nucleus, which was localized by extracellular recordings of the responses to natural peripheral stimulation. The presence of the calcium-binding proteins calbindin and paravalbumin in the projection neurons was detected by a double-labelling immunofluorescent method. The vast majority of the thalamic-projecting neurons contained paravalbumin, but not all parvalbumin-immunoreactive cells were retrogradely labelled. Calbindin-immunoreactive neurons were also found in the dorsal column nuclei, but only a small minority of these neurons projected to the thalamus. These findings are generally consistent with the notion that the different calcium-binding proteins represent functionally separate neuronal populations. Taken together with previous observations that parvalbumin is present in large dorsal root ganglion cells, which project to the dorsal column nuclei, and in the thalamocortical relay cells that receive dorsal column nuclear input, the present findings suggest that parvalbumin is associated with neurons that transmit modality-specific low-threshold mechanoreceptive information from the periphery to the somatosensory cortex. However, the presence of parvalbumin-immunoreactive cells that appeared not to project to the thalamus, as well as the occurrence of thalamic-projecting calbindin-immunoreactive neurons, indicate that parvalbumin and calbindin are present within several, functionally different, groups of neurons in the dorsal column nuclei.

Animals↗
PubMed1993

Evidence for calcium-binding proteins and calcium-dependent regulatory proteins in sensory cells of the organ of Corti.

Calcium is thought to play a major signaling role in outer hair cells to control metabolism, cytoskeletal integrity, cell shape and cell excitability. For this to happen, in resting cells the concentration of free calcium ions must be maintained at low levels so that focal increases can trigger specific events. In this paper, the localization of calcium, calcium-binding and calcium-dependent regulatory proteins in sensory cells from the guinea pig inner ear was demonstrated using immunocytochemical and histochemical techniques. We found the calcium buffer and/or calcium sensor proteins calmodulin, calbindin and calsequestrin predominantly in sensory cells and that when present, these proteins can be enriched in the outer hair cells. Calmodulin is found in the stereocilia, in the cuticular plate and in the cytoplasm and calbindin is found only in the cuticular plate and cytoplasm of both the inner and outer hair cells. The staining for these proteins in the outer hair cells is homogeneous, with no apparent compartmentalization along the lateral wall. Calsequestrin, thought to store and release calcium from membrane bound intracellular storage sites is found only in the cytoplasm of outer hair cells. There, it has a more punctuate staining pattern than does calmodulin or calbindin suggesting that it may be present in calciosomes rather than soluble in the cytoplasm. We did not detect caldesmon and S-100. Using the potassium pyroantimonate technique, we found precipitates containing calcium ions distributed throughout the cytoplasm of outer hair cells, with no evidence that the subsurface cisterns along the lateral wall act as calcium storage sites. Thus, calcium in resting cells is found in the cytoplasm along with calbindin and calmodulin and appears to have a punctate distribution consistent with a co-localization with calsequestrin. The implications of this distribution with respect to the slow shortening and elongation seen in outer hair cells are discussed.

Animals↗
PubMed1994

Purkinje-like cells in rat cochlear nucleus.

A unique class of cells, strongly immunopositive for anti-calbindin D-28 kDa was observed in and near the cochlear nucleus of young adult, male Sprague-Dawley rats. These cells are present in small numbers which are highly variable across animals and inconstant in position. They are preferentially located in the dorsal cochlear nucleus, with occasional examples being present in the ventral cochlear nucleus, as well as in adjacent brainstem locations. They have been referred to in other studies as displaced Purkinje cells or 'Purkinje cell-like cells', and are here designated 'Purkinje-like cells' (PLCs). PLCs have relatively large cell bodies, with thick, heavily spined dendrites, and are typically situated in an immediately subpial position. The dendritic arborization extends into the interior of the nucleus, away from the pial surface, a trajectory opposite in direction to that of the cerebellar Purkinje cells. The intense immunoreactivity exhibited by PLC somata and dendrites when treated with antiserum directed against calbindin is equivalent to that of cerebellar Purkinje cells, and markedly stronger than that of most other cell populations of the cochlear nucleus. However, in tissue treated with anti-parvalbumin, which also strongly labels cerebellar Purkinje cell somata and dendrites, PLC labeling, when present, is relatively weak, limited to the cell bodies and only the base of the dendrites of PLCs, indicating non-equivalence of the two cell types. In addition, the intensity of calbindin immunostaining in the PLCs appears to be more sensitive to glutaraldehyde in any of the fixative solutions than that seen in cerebellar Purkinje cells in the same sections. Of the cell types of the cochlear nucleus, the cartwheel cells would appear to be the most similar to the PLCs on morphological and immunocytochemical grounds. However, the subpial position and average somal dimensions of the PLCs, as well as the relatively modest immunoreactivity of the cartwheel cells for calbindin, rather clearly differentiate the PLCs from this class of neurons. The results of the present study suggest that the PLCs of the cochlear nucleus, although they may arise developmentally as ectopic cerebellar Purkinje cells and maintain certain Purkinje cell characteristics, represent a distinct neuronal cell type in the adult rat cochlear nucleus, exhibiting incomplete overlap of fixation, immunocytochemical and morphological characteristics with both cartwheel cells of the cochlear nucleus and cerebellar Purkinje cells.

Animals↗
PubMed2005

Effect of age, vitamin D, and calcium on the regulation of rat intestinal epithelial calcium channels.

Transepithelial transport of calcium involves uptake at the apical membrane, movement across the cell, and extrusion at the basolateral membrane. Active vitamin D metabolites regulate the latter two processes by induction of calbindin D and the plasma membrane ATPase (calcium pump), respectively. The expression of calbindin D and the calcium pump declines with age in parallel with transepithelial calcium transport. The apical uptake of calcium is thought to be mediated by the recently cloned calcium channels-CaT1 (or ECaC2, TRPV6) and CaT2 (or ECaC1, TRPV5). The purpose of these studies was to determine whether there were age-related changes in intestinal calcium channel regulation and to identify the dietary factors responsible for their regulation. Young (2 months) and adult (12 months) rats were fed either a high calcium or low calcium diet for 4 weeks. The low calcium diet significantly increased duodenal CaT1 and CaT2 mRNA levels in both age groups, but the levels in the adult were less than half that of the young. The changes in calcium channel expression with age and diet were significantly correlated with duodenal calcium transport and with calbindin D levels. To elucidate the relative roles of serum 1,25(OH)2D3 and calcium in the regulation of calcium channel expression, young rats were fed diets containing varying amounts of calcium and vitamin D. Dietary vitamin D or exogenous 1,25(OH)2D3 more than doubled CaT1 mRNA levels, and this regulation was independent of dietary or serum calcium. These findings suggest that the apical calcium channels, along with calbindin and the calcium pump, may play a role in intestinal calcium transport and its modulation by age, dietary calcium, and 1,25(OH)2D3.

Aging↗
PubMed2005

Neurogenesis and ontogeny of specific cell phenotypes within the hamster suprachiasmatic nucleus.

The hamster suprachiasmatic nucleus (SCN) is anatomically and functionally heterogeneous. A group of cells in the SCN shell, delineated by vasopressin-ergic neurons, are rhythmic with respect to Period gene expression and electrical activity but do not receive direct retinal input. In contrast, some cells in the SCN core, marked by neurons containing calbindin-D28k, gastrin-releasing peptide (GRP), substance P (SP), and vasoactive intestinal polypeptide (VIP), are not rhythmic with respect to Period gene expression and electrical activity but do receive direct retinal input. Examination of the timing of neurogenesis using bromodeoxyuridine indicates that SCN cells are born between embryonic day 9.5 and 12.5. Calbindin, GRP, substance P, and VIP cells are born only during early SCN neurogenesis, between embryonic days 9.5-11.0. Vasopressin cells are born over the whole period of SCN neurogenesis, appearing as late as embryonic day 12.5. Examination of the ontogeny of peptide expression in these cell types reveals transient expression of calbindin in a cluster of dorsolateral SCN cells on postnatal days 1-2. The adult pattern of calbindin expression is detected in a different ventrolateral cell cluster starting on postnatal day 2. GRP and SP expression appear on postnatal day 8 and 10, respectively, after the retinohypothalamic tract has innervated the SCN. In summary, the present study describes the ontogeny-specific peptidergic phenotypes in the SCN and compares these developmental patterns to previously identified patterns in the appearance of circadian functions. These comparisons suggest the possibility that these coincident appearances may be causally related, with the direction of causation to be determined.

Age Factors↗
PubMedDate not supplied

NMDA-induced 45Ca release in the dentate gyrus of newborn rats: in vivo microdialysis study.

This in vivo study, aimed at detecting the N-methyl-D-aspartate (NMDA) evoked Ca(2+)-induced Ca(2+) release from intracellular stores in the neonatal rat brain, demonstrates that the application of 5 mM N-methyl-D-aspartate via a microdialysis probe for 20 min to the dentate gyrus (DG) of halotane-anesthetized 7 day-old (postnatal day 7, PND 7) rats induces a prolonged decrease in Ca(2+) concentration in an initially calcium-free dialysis medium, indicative of a drop in the extracellular concentration of Ca(2+) and Ca(2+) influx to neurons. In parallel experiments, a huge NMDA-evoked release of 45Ca from the pre-labeled endogenous Ca(2+) pool was observed and interpreted as the expression of intracellular Ca(2+) release. Dantrolene (100 microM) significantly inhibited the NMDA-induced 45Ca release, whereas 250 microM ryanodine exerted an unspecific biphasic effect. Autoradiographic and immunocytochemical detection of ryanodine receptors and calbindin D(28K), respectively, in the hippocampal region of PND 7 rats displayed a pronounced expression of [3H]ryanodine binding sites in the DG, but only a slight immunoreactivity of calbindin D(28K). Plastic changes in neurons or excitotoxic neuronal damage induced by the activation of NMDA receptors are mediated by Ca(2+) signals, resulting from an influx of extracellular Ca(2+), and also in some neurons, from the release of intracellular Ca(2+). Our previous in vivo microdialysis experiments visualized NMDA-evoked 45Ca release in the adult rat dentate gyrus, attributable to Ca(2+)-induced Ca(2+) release from the ryanodine-sensitive pool. An additional role of calbindin in the mechanism of this phenomenon has been suggested. This aspect has not been studied in vivo in newborn rats. Our present results indicate that the release of 45Ca from the prelabeled intracellular, dantrolene-sensitive Ca(2+) pool in the DG neurons of immature rats, most probably representing a phenomenon of Ca(2+)-induced Ca(2+) release, significantly participates in the generation of NMDA receptor-mediated intracellular Ca(2+) signals, whereas the role of calbindin D(28K) in the mechanism of 45Ca release is negligible.

Animals↗
PubMed2002

Control of postganglionic neurone phenotype by the rat pineal gland.

As neurones develop they are faced with choices as to which genes to express, to match their final phenotype to their role in the nervous system. A number of processes can guide these decisions. Within the autonomic and sensory nervous systems, there are a handful of examples that suggest that one mechanism that may match phenotype to function is the presence of target-derived differentiation factors. We tested whether the rat pineal gland controls the expression of a neuropeptide (neuropeptide Y) and a calcium-binding protein (calbindin) in sympathetic postganglionic neurones that innervate it. We first showed that the chemical phenotype of sympathetic neurones innervating the rat pineal includes the expression of both neuropeptide Y and the calcium-binding protein, calbindin. After transplanting the pineal gland of neonatal rats into the submandibular salivary gland of neonatal hosts, it was innervated by sympathetic axons from the surrounding salivary gland tissue, which do not normally express neuropeptide Y and calbindin. The presence of the pineal gland led to the appearance of neuropeptide Y and calbindin in many of the postganglionic neurones that innervated the graft. From these findings we suggest that, like the rodent sweat gland, the pineal gland generates a signal that can direct the neurochemical phenotype of innervating sympathetic neurones.

Animals↗
PubMed1999

Learning-related fos-like immunoreactivity in the chick brain: time-course and co-localization with GABA and parvalbumin.

Previous work has shown that, after domestic chicks have learned the characteristics of an object (visual imprinting), there is a learning-related increase in the numerical density of Fos-immunopositive neurons in the intermediate and medial part of the hyperstriatum ventrale, a forebrain region that is a site of recognition memory for the imprinted object. The present study describes the time-course of this effect and has used double-labelling immunocytochemistry to identify neuronal types in which the effect occurs. Chicks were trained by exposure for 1 h to an imprinting (training) stimulus and then given a preference test to determine the strength of imprinting (i.e. of learning). Strongly imprinted chicks were killed 2, 2.5, 3, 3.5 or 4 h (12 chicks in each group) after the start of training and a further group of 12 chicks remained untrained. Sections from the chicks' brains were stained for Fos-like immunoreactivity, and the numerical density of Fos-positive nuclei in the intermediate and medial part of the hyperstriatum ventrale was counted. Relative to untrained chicks, there was a 60% increase in the number of Fos-positive nuclei in the intermediate and medial part of the hyperstriatum ventrale 2 h after the start of training (P = 0.02), but not at any other time. Sections from 10 trained chicks, two killed at each of the above times after training, and from two untrained chicks were stained with anti-Fos antibody as before and also with an antibody against GABA. Approximately 95% of the Fos-positive neurons in the intermediate and medial part of the hyperstriatum ventrale were also immunopositive for GABA. In neurons immunopositive for GABA, there were significantly (P = 0.02) more Fos-positive nuclei in the intermediate and medial part of the hyperstriatum ventrale 2 h after the start of training than in untrained chicks. Five chicks killed 2 h after training and five untrained chicks yielded sections for the next experiment; sections were double labelled for (i) Fos and (ii) either Calbindin-D28k or parvalbumin. Training gave rise to a significant (P = 0.017) increase in numerical density of Fos-positive nuclei of neurons that were immunonegative for Calbindin-D28k. This increase occurred in neurons that were immunopositive for parvalbumin. The use of alternative antibodies for GABA, Calbindin-D28k and parvalbumin in trained and untrained chicks confirmed the double-staining pattern observed in the quantitative experiments. The results demonstrate that the learning-related increase in Fos-like immunoreactivity following training is transitory and have localized the increase to a population of neurons immunopositive for GABA and parvalbumin, but not Calbindin-D28k.

Animals↗
PubMed1998

Regulation of osteopontin gene expression during egg shell formation in the laying hen by mechanical strain.

The aim of this study is to evaluate the regulation of the osteopontin (OPN) gene expression by non-hormonal stimuli, such as calcium flux and mechanical strain during the daily egg cycle in the oviduct of the laying hen. After the egg enters the eggshell gland (ESG), the OPN gene is expressed by the epithelium cells in two waves: first by the basal cells and only then by the apical cells of the epithelium. A reduction in OPN gene expression was observed 1 h prior to laying. The calbindin gene, which marks the onset of calcification, was found to be expressed in the glandular epithelium starting 2 h after OPN gene expression. In addition, the formation of soft shells was accompanied by a reduction in calbindin, but not in OPN, gene expression. The application of a mechanical strain comparable to that induced by an egg led to induction of OPN gene expression at a normally quiescent phase in the cyclical expression of this gene. The induction of the gene was time- and strain-dependent and temporally similar to that induced by the entry of the egg into the ESG. In contrast, the calbindin gene was not affected by mechanical strain. The ESG of the laying hen provides a system to study the effect of a mechanical strain on matrix protein production in vivo, in a relevant physiological setting. The finding suggests that, in contrast to calbindin, OPN gene expression is not regulated by calcium flux but rather by the mechanical strain imposed by the resident egg.

Animals↗
PubMed2000

The distribution and origin of the calretinin-containing innervation of the nucleus accumbens of the rat.

The nucleus accumbens of the rat consists of several subregions that can be distinguished on the basis of histochemical markers. For example, the calcium-binding protein calbindin D28k is a useful marker of the core compartment of the nucleus accumbens. Calretinin, another calcium-binding protein, is found in a dense fibre plexus in the accumbal shell and septal pole regions. The source of the accumbal calretinin innervation is not known. We examined the distribution of calretinin in the nucleus accumbens and used tract-tracing and lesion methods to determine the source of this calretinin innervation. Intense calretinin immunoreactivity was present in the medial shell, but the density of calretinin axons diminished sharply in the ventrolateral shell. Regions of dense calretinin immunostaining and those areas with calbindin-like immunoreactive cell bodies were generally segregated in the nucleus accumbens, although some overlap in the transition region between the core and shell was seen. Small clusters of calretinin-immunoreactive fibres were seen in the core, where they were restricted to calbindin-negative patches. Injections of the anterograde tracer biotinylated dextran amine into the paraventricular thalamic nucleus labelled fibres in calretinin-rich regions of the accumbens. Conversely, injections of Fluoro-gold into the accumbal shell retrogradely labelled numerous cells in the paraventricular thalamic nucleus that were calretinin-immunoreactive. Electrolytic lesions of the paraventricular thalamic nucleus reduced calretinin levels in the shell by approximately 80%. These data indicate that the calretinin innervation of the nucleus accumbens is derived primarily from the thalamic paraventricular nucleus, and marks accumbal territories that are largely complementary to those defined by calbindin.

Afferent Pathways↗
PubMed1999

The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease.

To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D(28K) immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions ('matrix') and in five calbindin-poor pockets ('nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.

Aged↗
PubMed1992

Facilitated diffusion of calcium across the rat intestinal epithelial cell.

Similarities and differences between the models for facilitated diffusion of substrates across cytoplasm and across cell membranes are discussed. It is valuable to consider that calbindin acts to increase the partitioning of calcium within the cytoplasm. Calculations on the basis of a simple model for this facilitated diffusion show that the rate of transcellular calcium movement depends in a complex way on KCAB, the dissociation constant for calcium and calbindin. At each value of the transcellular concentration gradient of free calcium, there is an optimal value of KCAB that gives the maximal augmentation of calcium flow. For low values of the ratio of free calcium concentrations at the opposite poles of the cell, the optimal value of KCAB is close to the prevailing concentration of free calcium. An analysis of possible effects of pH on binding of calcium to calbindin shows that it may be useful to consider cotransport of calcium and protons within the cell. Small values of a transcellular pH gradient can have large effects on enhancing transcellular calcium flow, provided the hydrogen ion concentration affects the binding of calcium to calbindin or the rate of diffusion of the calcium/calbindin complex.

Animals↗
PubMed1994

Chemical compartmentation and relationships between calcium-binding protein immunoreactivity and layer-specific cortical caudate-projecting cells in the anterior intralaminar nuclei of the cat.

Neurons projecting to the parietal cortex or striatum and neurons showing immunoreactivity for the calcium-binding proteins parvalbumin and 28KD-calbindin were examined in the anterior intralaminar nuclei (IL) of the cat. Retrograde tracing from deep or superficial parietal cortical layers or from the caudate nucleus was coupled with immunohistochemistry to determine which of these proteins were expressed in the projection neurons. It was found that IL neurons project to deep as well as to superficial layers of the parietal cortex, that IL-cortical neurons could be differentiated into two populations according to their cortical projection pattern and their soma size, and that IL neurons projecting to the parietal cortex or to the striatum express 28KD calbindin immunoreactivity but not parvalbumin immunoreactivity. The distribution of immunoreactivity to 28KD calbindin and parvalbumin in the neuropil showed a consistent complementary distribution pattern in the IL. The compartments based on differential parvalbumin and 28KD calbindin expression may indicate the presence of functionally segregated units in IL.

Animals↗
PubMed1999

Pathogenesis of fetal hypomineralization in diabetic rats: evidence for delayed bone maturation.

There is some evidence that fetuses of diabetic rats (FDR) are hypomineralized. To explore the pathogenic role of decreased maternal duodenal Ca absorption, fetal hypotrophy, and decreased placental calbindin-D9K, respectively, spontaneously diabetic rats fed a 1.0% Ca diet were compared with diabetic rats treated with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (15 ng/ 100 g) during week 3 of pregnancy, which restored duodenal calbindin-D9K concentrations to normal; with nondiabetic rats semistarved during week 3, which resulted in similar fetal hypotrophy; and with nondiabetic rats fed high cation diets (1.5% Ca-1.5% Sr and 1.5% Ca-3.5% Sr) during week 3, the latter of which repressed duodenal and placental calbindin-D9K toward concentrations measured in diabetic rats. In addition, fetal tibiae were studied histologically. Ca content was lower in 21.5-d-old FDR than in control fetuses. FDR had lower plasma osteocalcin (OC) levels and, on histomorphometry, increased hypertrophic cartilage width, indicating retarded bone maturation. Maternal 1,25(OH)2D3 treatment did not change Ca content and hypertrophic cartilage width in FDR. Fetuses of semistarved rats had plasma OC levels and hypertrophic cartilage width comparable to those of control fetuses. Fetuses of rats fed the 1.5% Ca-3.5% Sr diet were more severely hypomineralized than FDR but had higher plasma OC than both FDR and control fetuses, compatible with fetal Ca deficiency. Whereas diabetic placentas showed weak but homogeneous staining of calbindin-D9K in the labyrinth on immunohistology, degenerative zones were present in placentas of rats fed the 1.5% Ca-3.5% Sr diet. Thus, there is no mineralization defect in FDR caused by disturbed maternal duodenal Ca absorption or transplacental Ca transport, but a delay in bone maturation that is unexplained by their lower body weight.

Animals↗
PubMed1993

The mechanism for the disparate actions of calcitriol and 22-oxacalcitriol in the intestine.

22-Oxacalcitriol (OCT) is one of several new analogs of vitamin D that retain many of the therapeutically useful properties of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], but have much less calcemic activity. In the present study we examined the actions of OCT on intestinal calcium absorption and calbindin D9k mRNA in vitamin D-deficient rats. After ip injection of OCT (1 microgram/kg), calcium absorption increased significantly by 2 h and was maximal at 4 h (2.5-fold above control), but returned to pretreatment levels by 16 h. In contrast, the same dose of 1,25-(OH)2D3 caused a 3-fold increase in calcium absorption, which lasted more than 48 h. The transient effect of OCT on calcium absorption was also observed when the analog was infused at a dose of 1 micrograms/kg.day for 3 days. At the end of the infusion period, calcium absorption was 3-fold higher than that in vehicle-infused controls, but fell to pretreatment levels by 24 h after removing the minipumps. The time courses for induction of calbindin D9k mRNA were similar for OCT and 1,25-(OH)2D3, with no change observed until more than 4 h after injection. However, calbindin mRNA levels returned to pretreatment values more rapidly in the OCT-treated rats. Consistent with these findings, we observed that a 1 microgram/kg dose of [3H] OCT was completely cleared by 4-6 h after injection. This was paralleled by a loss of [3H]OCT associated with the intestinal vitamin D receptor. The rapid clearance of OCT is probably due to its low affinity for the serum vitamin D-binding protein. This low affinity would also be expected to allow greater accessibility to target cells. In support of this, we found that higher amounts of OCT than 1,25-(OH)2D3 were associated with the intestinal vitamin D receptor after the injection of several doses of these tritiated ligands. In summary, our results indicate that the pharmacokinetic properties of OCT are responsible at least in part for its low calcemic activity. Furthermore, comparison of the transient elevation of calcium absorption by OCT with its more prolonged effects on PTH and calbindin D9k indicates that each action of vitamin D compounds has a distinct biological half-life. The short circulating half-life of OCT can exploit these differences to provide a therapeutic advantage in the treatment of vitamin D-responsive diseases.

Animals↗
PubMed2004

Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats.

UNLABELLED: The functional status and mechanism of increased VDR in GHS rats were investigated. Basal VDR and calbindins were increased in GHS rats. 1,25(OH)(2)D(3) increased VDR and calbindins in controls but not GHS rats. VDR half-life was prolonged in GHS rats. This study supports the mechanism and functional status of elevated VDR in GHS rats. INTRODUCTION: Genetic hypercalciuric stone-forming (GHS) rats form calcium kidney stones from hypercalciuria arising from increased intestinal calcium absorption and bone resorption and decreased renal calcium reabsorption. Normal serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels and increased vitamin D receptor (VDR) protein suggest that high rates of expression of vitamin D-responsive genes may mediate the hypercalciuria. The mechanism of elevated VDR and state of receptor function are not known. MATERIALS AND METHODS: GHS and non-stone-forming control (NC) male rats (mean, 249 g), fed a normal calcium diet, were injected intraperitoneally with 1,25(OH)2D3 (30 ng/100 g BW) or vehicle 24 h before cycloheximide (6 mg/100 g, IP) and were killed 0-8 h afterward. Duodenal VDR was measured by ELISA and Western blot, and duodenal and kidney calbindins (9 and 28 kDa) were measured by Western blots. RESULTS AND CONCLUSIONS: Duodenal VDR protein by Western blot was increased 2-fold in GHS versus NC rats (633 +/- 62 versus 388 +/- 48 fmol/mg protein, n = 4, p < 0.02), and 1,25(OH)2D3 increased VDR and calbindins (9 and 28 kDa) further in NC but not GHS rats. Duodenal VDR half-life was prolonged in GHS rats (2.59 +/- 0.2 versus 1.81 +/- 0.2 h, p < 0.001). 1,25(OH)2D3 prolonged duodenal VDR half-life in NC rats to that of untreated GHS rats (2.59 +/- 0.2 versus 2.83 +/- 0.3 h, not significant). This study supports the hypothesis that prolongation of VDR half-life increases VDR tissue levels and mediates increased VDR-regulated genes that result in hypercalciuria through actions on vitamin D-regulated calcium transport in intestine, bone, and kidney.

Animals↗