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PubMed2004

Calcium bioavailability and kinetics of calcium ascorbate and calcium acetate in rats.

The objective was to investigate the bioavailability and mechanism of calcium absorption of calcium ascorbate (ASC) and calcium acetate (AC). A series of studies was performed in adult Sprague-Dawley male rats. In the first study, each group of rats (n = 10/group) was assigned to one of the five test meals labeled with (45)Ca: (i) 25 mg calcium as heated ASC or (ii) unheated ASC, (iii) 25 mg calcium as unheated AC, (iv) 3.6 mg Ca as unheated ASC, or (v) unheated AC. Femur uptake indicated better calcium bioavailability from ASC than AC at both calcium loads. A 5-min heat treatment partly reduced bioavailability of ASC. Kinetic studies were performed to further investigate the mechanism of superior calcium bioavailability from ASC. Two groups of rats (n = 10/group) received oral doses of 25 mg Ca as ASC or AC. Each dose contained 20 micro Ci (45)Ca. Two additional groups of rats (n = 10/group) received an intravenous injection (iv) of 10 micro Ci (45)Ca after receiving an unlabeled oral dose of 25 mg calcium as ASC or AC. Sequential blood samples were collected over 48 hrs. Urine and fecal samples were collected every 12 hrs for 48 hrs and were analyzed for total calcium and (45)Ca content. Total calcium and (45)Ca from serum, urine, and feces were fitted by a compartment kinetics model with saturable and nonsaturable absorption pathways by WinSAAM (Windows-based Simulation Analysis and Modeling). The difference in calcium bioavailability between the two salts was due to differences in saturable rather than passive intestinal absorption and not to endogenous secretion or calcium deposition rate. The higher bioavailability of calcium ascorbate was due to a longer transit time in the small intestine compared with ASC.

Absorption↗

PubMed1999

[The key to the calcium regulation and calcium metabolism: G protein coupled membrane calcium receptor].

CALCIUM RECEPTOR: The calcium receptor can ìperceiveî small vanations in extracellular calcium concentrations and adapt cell response. The ìcalciostatî was hypothesized for several years before its discovery on parathyroid and other cells, particularly renal cells. It can couple with protein G and has 7 transmembrane domains. FUNCTION: The calcium receptor is stimulated by increased extracellular calcium level which, via a GDP/GTP exchange by the heterotrimeric protein G and a transduction network, triggers release of intracellular calcium ion stores and influx of extracellular calcium ions through the cationic channels. A FUNDAMENTAL ROLE: The calcium receptor controls not only parathormone and thyrocalcitonin secretion, but also plays an important role in calcium transfer from the mother to fetus, in reabsorption of calcium by the large ascending cortial portion of the Henlé loop, and in reabsorption of water by the collecting tubes. DISEASE STATES: Mutations affecting the calcium receptor sequence cause hereditary or familial parathyroid diseases. In addition, decreased expression of the calcium receptor protein and signal has been demonstrated in primary hyperparathyroidism as well as in secondary hyperparathyroidism. The calcium receptor is also expressed in a large variety of tissues and could be implication in other disease states. THERAPEUTICS: Medical treatment of primary hyperparathyroidism using specific calcium receptor agonists derived from phenylalkylamines is now possible. The efficacy of these drugs should be demonstrated in the treatment of secondary hyperparathyroidism and chronic renal failure. Other therapeutic implications are possible.

Animals↗

PubMed1989

A model of propagating calcium-induced calcium release mediated by calcium diffusion.

The effect of sudden local fluctuations of the free sarcoplasmic [Ca++]i in cardiac cells on calcium release and calcium uptake by the sarcoplasmic reticulum (SR) was calculated with the aid of a simplified model of SR calcium handling. The model was used to evaluate whether propagation of calcium transients and the range of propagation velocities observed experimentally (0.05-15 mm s(-1)) could be predicted. Calcium fluctuations propagate by virtue of focal calcium release from the SR, diffusion through the cytosol (which is modulated by binding to troponin and calmodulin and sequestration by the SR), and subsequently induce calcium release from adjacent release sites of the SR. The minimal and maximal velocities derived from the simulation were 0.09 and 15 mm s(-1) respectively. The method of solution involved writing the diffusion equation as a difference equation in the spatial coordinates. Thus, coupled ordinary differential equations in time with banded coefficients were generated. The coupled equations were solved using Gear's sixth order predictor-corrector algorithm for stiff equations with reflective boundaries. The most important determinants of the velocity of propagation of the calcium waves were the diastolic [Ca++]i, the rate of rise of the release, and the amount of calcium released from the SR. The results are consistent with the assumptions that calcium loading causes an increase in intracellular calcium and calcium in the SR, and an increase in the amount and rate of calcium released. These two effects combine to increase the propagation velocity at higher levels of calcium loading.

Calcium↗

PubMed1999

Multiple effects of econazole on calcium signaling: depletion of thapsigargin-sensitive calcium store, activation of extracellular calcium influx, and inhibition of capacitative calcium entry.

The effect of econazole on intracellular calcium levels ([Ca2+]i) in Madin Darby canine kidney cells was investigated using fura-2 fluorimetry. Econazole increased [Ca2+]i dose-dependently at 5-50 microM. The Ca2+ signal consisted of an initial rise, a gradual decay and a sustained plateau. Extracellular Ca2+ removal partially reduced the econazole response. Mn2+ quench of fura-2 fluorescence confirmed econazole-induced Ca2+ influx. The econazole-sensitive intracellular Ca2+ store overlaps with that sensitive to thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+ pump, because 25 microM econazole depleted the thapsigargin-sensitive store, and conversely, thapsigargin abolished the econazole response. Econazole (25-50 microM) partially inhibited capacitative Ca2+ entry induced by cyclopiazonic acid, another endoplasmic reticulum Ca2+ pump inhibitor, measured by depleting internal Ca2+ store in Ca(2+)-free medium followed by adding 10 mM CaCl2. Econazole induced capacitative Ca2+ entry itself. Pretreatment with La3+ (100 microM) partially inhibited 25 microM econazole-induced Mn2+ quench of fura-2 fluorescence, and La3+ immediately reduced 20 microM econazole-induced Ca2+ signal when added at the peak of the signal, suggesting that econazole induced Ca2+ influx via two separate pathways: one is sensitive to La3+, the other is not. La3+ enlarged 25 microM econazole-induced [Ca2+]i transient during the decay phase. The econazole response was not altered when the cytosolic level of inositol 1,4,5-trisphosphate was inhibited by the phospholipase C inhibitor U73122.

Animals↗

PubMed2004

Comparison of the effects of calcium loading with calcium citrate or calcium carbonate on bone turnover in postmenopausal women.

Calcium supplementation is known to increase bone mineral density and decrease fractures, but the relative efficacy of different forms of calcium supplementation is not established. We compared the effects of calcium carbonate and calcium citrate on markers of bone resorption in older postmenopausal women in an open-labeled crossover study. Forty women were randomized to receive 1000 mg/day of either calcium citrate or calcium carbonate for 12 weeks, followed by a 2-week washout without calcium supplements and 12 weeks treatment with the alternate calcium supplement. All women received vitamin D (900 IU/day). Thirty-four women (25 Caucasian, nine Hispanic) completed the study. No significant differences in the decrease in parathyroid hormone (PTH) or bone specific alkaline phosphatase or the increase in urinary calcium/creatinine were detected between the two treatments. However, calcium citrate supplementation decreased the collagen cross-link resorption markers, urinary N-telopeptide (-30%), C-telopeptide (-31%), free deoxypyridinoline (19%) and serum N-telopeptide (-8%), compared to no significant change following calcium carbonate supplementation (+2%, +3%, +2% and +2%, respectively; P<0.05). Calcium citrate decreased markers of bone resorption significantly more than calcium carbonate in postmenopausal women, although no differences in their effects in calcium excretion or PTH were detected.

Aged↗

PubMed1999

Acute effects of calcium sodium citrate supplementation of a test meal on mineral homeostasis, oxalate, and calcium oxalate crystallization in the urine of healthy humans--preliminary results in patients with idiopathic calcium urolithiasis.

Calcium, in the form of regular food supplementation, can improve bone metabolism, but it can also increase the risk for renal calcium stones, and may aggravate pre-existing calcium urolithiasis. To study the first of these two aspects, ten healthy volunteers were given a conventional test meal (breakfast; calcium content 28 mg) with or without two dosages of calcium (as calcium-sodium citrate, CSC 1, 680 mg; CSC 2 1,360 mg), taken after an overnight 12 h fast. To study the latter aspect, patients with idiopathic recurrent calcium urolithiasis (ICU) received a balanced test meal of fixed composition, containing 1,000 mg calcium either as CSC (Meal + CSC3; n = 6) or as calcium gluconate (Mcal; n = 8). In normals, CSC induced a dose-dependent increasing intestinal absorption of calcium, and a decrease in oxalate absorption; in serum, CSC increased calcitonin and suppressed parathyroid hormone, but left unchanged the markers of bone turnover, serum osteocalcin and bone alkaline phosphatase. In urine, CSC decreased bone resorption markers (collagen crosslinks) and phosphaturia increased citrate, created signs of metabolic alkalosis, and inhibited several parameters of CaOx crystallization. In ICU, the CSC3 load failed to promote the crystallization of CaOx and calcium phosphate. It was concluded that CSC supplementation of a meal: (1) is well tolerated by healthy subjects and ICU patients, renders calcium highly available to bone, and prevents post-prandial oxaluria from rising; and, (2) is followed by the inhibition of crystallization of renal stone forming calcium-containing substances. Long-term studies aimed at evaluating the usefulness of CSC in preserving healthy bone, and in the metaphylaxis of renal stones would appear justified.

Adult↗

PubMed1998

Relationship between intracellular calcium store depletion and calcium release-activated calcium current in a mast cell line (RBL-1).

The kinetic relationship between depletion of endoplasmic reticulum calcium stores and the activation of a calcium release-activated calcium current (Icrac) was investigated in the RBL-1 mast cell line. The inositol trisphosphate receptor activator, inositol 2,4, 5-trisphosphate ((2,4,5)IP3), the sarcoplasmic-endoplasmic reticulum calcium ATPase inhibitor, thapsigargin, and the calcium ionophore, ionomycin, were used to deplete stored calcium. For (2,4,5)IP3 and thapsigargin, a significant delay was observed between the initiation of calcium store depletion and the activation of Icrac. However, for ionomycin, little or no delay was observed. This may indicate that a specialized subcompartment of the endoplasmic reticulum functions as a regulator of calcium entry and that this compartment is relatively resistant to depletion by (2,4,5)IP3 and thapsigargin but not to depletion by ionomycin. For all three calcium-depleting agents, the rate of development of Icrac, once initiated, was relatively constant, suggesting an all-or-none mechanism. However, there were also clear experimental situations in which submaximal, graded depletion of stored calcium resulted in submaximal activation of Icrac. This complex behavior could also result from the existence of a specific subcompartment of endoplasmic reticulum regulating Icrac. The kinetic behavior of this compartment may not be accurately reflected by the kinetics of calcium changes in the bulk of endoplasmic reticulum. These findings add to the growing body of evidence suggesting specialization of the endoplasmic reticulum calcium stores with regard to the control of capacitative calcium entry.

Animals↗

PubMed2002

Ultralow calcium requirements of fungi facilitate use of calcium regulating agents to suppress host calcium-dependent defenses, synergizing infection by a mycoherbicide.

Infection by many fungi activates a variety of calcium dependent defenses in the hosts, slowing or suppressing the attacker and limiting the efficacy of mycoherbicides. The calcium requirement for fungal growth is so low that it could only be implied based on fungi containing calcium-dependent signaling enzymes. Analytical grade media contain <2 microM calcium, and the addition of specific chelators does not affect fungal growth. Hydrophobic derivatives of the calcium-specific chelator BAPTA designed to traverse plant cuticles were synthesized in order to chelate calcium internally during fungal attack. Some chelators as well as calcium precipitating oxalate and channel blocker verapamil were applied with a weakly mycoherbicidal Colletotrichum coccodes to cotyledons of compatible Abutilon threophrasti. They suppressed calcium dependent callose biosynthesis in the weed and increased virulence but may have affected other calcium-dependent processes that facilitate virulence. The low calcium requirement of fungi, and their high affinity for calcium, allows the application of calcium-regulating agents as synergists for mycoherbicides where the weed uses calcium-dependent defenses.

Calcium↗

PubMed1996

Bioavailability of calcium supplements and the effect of Vitamin D: comparisons between milk, calcium carbonate, and calcium carbonate plus vitamin D.

Our aim was to examine a regimen for calcium supplementation because various factors seem to be important for its bioavailability, and to examine the effect of adding vitamin D to the supplement. The participants were 20 healthy women aged 28-59 y (chi: 38 y). During the 3-d periods and 1 d before, the participants were consuming a calcium and energy-balanced diet as similar to their usual daily diet as possible. The study was designed as a randomized, placebo-controlled, partly blinded crossover study divided into four periods of 3 d each: 1) three tablets containing 1000 mg CaCO3/d, 2) three tablets containing 1000 mg CaCO3 plus 5 micrograms (200 IU) vitamin D/d, 3)1 L more milk than in the usual daily diet, and 4) three placebo tablets daily. Bioavailability of the different calcium-supplement regimens were evaluated by changes in 24-h urinary excretion of calcium, phosphate, and magnesium. A significant increase in urinary calcium excretion was found during all periods of supplementation compared with the placebo period (P<0.01). Excretion of calcium in the calcium carbonate period was not significantly higher that that in the milk period, but calcium carbonate plus vitamin D resulted in significantly higher calcium excretion compared with that in the milk period. We conclude that the examined calcium carbonate regimen is at least as good a calcium supplement as milk, and that addition of 600 IU vitamin D/d promptly resulted in an increase in urinary calcium excretion after an increase in calcium absorption, even in healthy women.

Adult↗

PubMed1985

Ryanodine as a tool to determine the contributions of calcium entry and calcium release to the calcium transient and contraction of cardiac Purkinje fibers.

Our object was to assess the relative roles of transsarcolemmal calcium entry and intracellular calcium release in the contraction of cardiac Purkinje fibers. We observed intracellular calcium transients, membrane potential, and contraction in aequorin-injected canine cardiac Purkinje fibers exposed to highly selective pharmacological modifiers of excitation-contraction coupling. To influence selectively the release of calcium from the sarcoplasmic reticulum, we used the plant alkaloid, ryanodine. To influence calcium entry, selectively, we used either the calcium channel antagonist, nitrendipine, or the calcium channel agonist, Bay k 8644. Ryanodine alone (1 microM) reduced both components of the intracellular aequorin luminescence signal (L1 and L2). In three muscles, the luminescence signals were 3% of control in amplitude (standard error of the mean, 2%) without two distinct components and the twitch tension was 2% of control (standard error of the mean, 3%), whereas the action potential was prolonged. The aequorin signal and twitch remaining in ryanodine were abolished by the calcium antagonist nitrendipine (10 microM), which also lowered the action potential plateau, consistent with the block of functional calcium channels. In two experiments, the calcium-channel agonist, Bay k 8644, in the presence of ryanodine, increased the aequorin luminescence and the contraction, but only to a very small fraction of their control values. Sodium withdrawal in potassium-free, ryanodine-containing solution produced large slow increases in calcium and tension, showing that tension could still be produced, that aequorin remained functional, and that sodium/calcium exchange was not inhibited by ryanodine. Caffeine increased intracellular calcium, showing that calcium stores were not depleted.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1975

The role of the parathyroids for the adaptation to a low calcium intake. 3. The long-term effect of parathyroidectomy on the adaptation to a low calcium intake in adult rats with special reference to plasma calcium, bone tissue and adrenal glands.

One-year-old selectively parathyroidectomized rats responded with a plasma calcium reduction to below 4.1 mEq./1 in 86 per cent at a normal and in 100 per cent at a low dietary calcium intake. Among the former, 17 per cent normalized their plasma calcium level within 8 weeks and another 40 per cent between the 8th ana 27th week of observation. Among the latter, only 10 per cent showed a normalization and first after the long-term period of observation. On the normal level of dietary calcium the parathyroidectomized animals with persistently reduced plasma calcium showed a significantly increased bone mass which was paradoxical in view of their inability of adaptation. On the low level of dietary calcium a normal bone resorptive activity was maintained despite parathyroidectomy possibly through the action of increased levels of 1,25-dihydroxycholecalciferol provoked by the profoundly reduced plasma calcium. This was, however, insufficient for adaptation and no osteoporosis developed. For the adaptation to a reduced calcium intake skeletal calcium reserves had to become mobilized through the action of the parathyroids with resulting osteoporosis. This was brought about by increased mobilization of skeletal calcium with resulting osteoporosis, a phenomenon which could be seen also among the parathyroidectomized animals on a low dietary calcium and with a normalized plasma calcium level. This osteoporosis was similar to that found in the calcium deficient intact animals. The described bone changes were progressing in character and there was no major influence by any eventual effect on bone growth. At histological and morphometric analyses of the adrenal cortex no apparent changes were found after parathyroidectomy.

Adaptation, Physiological↗

PubMed1976

[Studies on calcium absorption out of a calcium-vitamin-D-preparation using calcium-47 (author's transl)].

Calcium absorption in man was studied by means of labelling an ampoule of Frubiase Calcium forte with calcium-47. For comparative purpose a solution containing the same amount of calcium salts as the ampoule was labelled as well. Already 10 minutes after oral administration of Ca-47 in 10 ml of Frubiase Calcium forte radioactivity was statistically significant measurable in blood. At the same time there was no significant radioactivity demonstrable out of the calcium salt solution. Between 45 and 120 minutes following oral application of the isotope both groups showed a statistically significant difference concerning the measurable blood activity. The Frubiase Calcium forte values were always higher, especially one and two hours after administration of the radiocalcium (up to 40%). The levels at these times correlate well with the total calcium absorption. Measurements over the compact bone region of the ankle demonstrated significantly higher values of calcium-47 in case of Frubiase Calcium forte compared with the calcium salt solution. These findings indicate in the case of Frubiase Calcium forte a higher bone mineral accretion. There is a good direct proportionality between the amount of these values and the total calcium absorption.

Adult↗

PubMed1997

The effect of calcium gluconate and other calcium supplements as a dietary calcium source on magnesium absorption in rats.

The effects of commercially available calcium supplements (calcium carbonate, calcium gluconate, oyster shell preparation and bovine bone preparation) and gluconic acid on the absorption of calcium and magnesium were evaluated for 30 days in male Wistar rats. There were no differences in the apparent absorption ratio of calcium among rats fed each calcium supplement; however, the rats fed the calcium gluconate diet had a higher apparent absorption ratio of magnesium than the rats fed the other calcium supplements. Dietary gluconic acid also more markedly stimulated magnesium absorption than the calcium carbonate diet, and the bone (femur and tibia) magnesium contents of rats fed the gluconic acid diet were significantly higher than those of the rats fed the calcium carbonate diet. Furthermore, the weight of cecal tissue and the concentrations of acetic acid and butyric acid in cecal digesta of rats fed the calcium gluconate diet or the gluconic acid diet were significantly increased. We speculate that the stimulation of magnesium absorption in rats fed the calcium gluconate diet is a result of the gluconic acid component and the effect of gluconic acid on magnesium absorption probably results from cecal hypertrophy, magnesium solubility in the large intestine and the effects of volatile fatty acids on magnesium absorption.

Absorption↗

PubMed2002

A novel type of milk calcium has higher calcium bioavailability compared with the hydroxyapatite type of milk calcium.

We prepared a novel type of milk calcium from milk whey, and evaluated its calcium bioavailability as compared with conventional industrial milk calcium obtained from milk whey, which has been reported to be an excellent calcium source. An X-ray diffraction analysis showed that the chemical form of conventional industrial milk calcium from milk whey through the neutralization and precipitation method (NP-MCa) is hydroxyapatite type, and that of a novel type of milk calcium obtained using the ultrafiltration method (UF-MCa) is different from hydroxyapatite. Growing rats were fed either NP-MCa or UF-MCa as the source of calcium for 33 d. The calcium absorption rate in the UF-MCa diet group was significantly higher than that in the NP-MCa diet group. The calcium content of the femur in the UF-MCa diet group was significantly higher than that in the NP-MCa diet group. The breaking force of the excised femur in the UF-MCa diet group was also significantly higher than that in the NP-MCa diet group. The serum calcium level, alkaline phosphatase activity and calcitonin level were not significantly different between the experimental groups, but the PTH level of the serum in the UF-MCa diet group was significantly lower than that in the NP-MCa diet group. These results indicate that the calcium bioavailability of the novel type of milk calcium (UF-MCa) is higher than that of the hydroxyapatite type of milk calcium (NP-MCa).

Alkaline Phosphatase↗

PubMed1990

Changes in intact parathyroid hormone levels during hemodialysis following exposure to either differing dialyzate calcium concentrations or calcium-free dialysis with varying calcium infusion rates.

To determine the optimal infusion rate for calcium, when using a dialyzate which was calcium free, six patients were treated sequentially, in random order, with six different dialyzates. Three were calcium free and they were infused with replacement calcium at either 10, 15 or 20 ml/hour using 10% CaCl2. The other three used standard bicarbonate dialyzate with either 1.25, 1.5 or 1.75 mmol/l calcium. Ionized calcium and intact parathyroid hormone (Nichols IRMA PTH) were measured at the start and end of each dialysis. Ionized calcium rose slightly with 15 ml/hour calcium infusion and PTH fell 137 +/- 111 pg/ml. These changes were similar to those of 1.5 mmol/l calcium in standard bicarbonate. More PTH suppression and higher end dialysis calcium resulted from 20 ml/hour infusion or 1.75 mmol/l dialyzate calcium. It was concluded that 15 ml/hour is a suitable calcium infusion rate under normal conditions when using calcium-free dialyzate.

Analysis of Variance↗

PubMed1996

Capacitative calcium entry is colocalised with calcium release in Xenopus oocytes: evidence against a highly diffusible calcium influx factor.

Depletion of intracellular calcium stores activates the plasma membrane capacitative calcium entry pathway in many cell types. The nature of the signal that couples the depletion of the intracellular calcium stores to the activation of the plasma membrane calcium influx pathway is as yet unknown. It has recently been suggested that a highly diffusible calcium influx factor is involved in the activation of capacitative calcium entry, and that its action is potentiated by the protein phosphatase inhibitor okadaic acid. Depletion of intracellular calcium stores in a localised region of a Xenopus oocyte was found to evoke capacitative calcium entry exclusively colocalised across the stimulated area of the plasma membrane, arguing against the involvement of a highly diffusible calcium influx factor. Equally, no evidence could be found for the presence of a soluble calcium influx factor in the bulk cytosol of Xenopus oocytes. The potentiation of capacitative calcium entry by okadaic acid resembled that mediated by the activation of protein kinase C, thus suggesting that okadaic acid activity may not necessarily be related to the action of a putative calcium influx factor.

Animals↗

PubMed1996

Agonist-releasable intracellular calcium stores and the phenomenon of store-dependent calcium entry. A novel hypothesis based on calcium stores in organelles of the endo- and exocytotic apparatus.

Store-dependent calcium entry represents a little characterized calcium permeation pathway that is present in a variety of cell types. It is activated in an unknown way by depletion of intracellular calcium stores, for example in the course of phospholipase C stimulation. Current hypotheses propose that depleted calcium stores signal their filling state to this permeation pathway either by direct, protein-mediated interaction or by release of a small, diffusible messenger. The further characterization of store-dependent calcium entry will benefit from progress in the identification of the intracellular calcium storing compartments. Recent findings reviewed here suggest that these compartments include parts of the organelle system that is involved in endo- and exocytosis. This commentary describes a novel model of store-dependent calcium entry based on calcium stores belonging to the endo- and exocytotic organelle system. Such calcium stores could establish a tubule-like connection with the extracellular space, in analogy to the cellular compartments that contain the insulin-sensitive glucose transporter or the gastric proton pump. This connection will provide a pathway for store-dependent calcium entry. Under store depletion, extracellular calcium will permeate through the tubule-like connection into the store lumen and from there into the cytosol. The consequences of this model for the development of drugs modulating store-dependent calcium entry are discussed.

Animals↗

PubMed1992

Prevention of calcium overload and down-regulation of calcium channels in rat heart by SR 33557, a novel calcium entry blocker.

The effect of SR 33557, a novel calcium entry blocker, on calcium overload, and regulation of calcium channels and beta-adrenergic receptors was investigated in the rat heart. Calcium overload and infarct-like lesions were produced by a large dose of isoproterenol (40 mg/kg, subcutaneously) to rats. Calcium overload was maximal 8 hours after administration of isoproterenol (control: 5.7 mmol Ca2+/kg dry weight, isoproterenol: 34.9 mmol Ca2+/kg dry weight). At that time, a decrease in the total number of beta-adrenergic receptors (-27%) and calcium channels (-20% and -23%) was observed. Intravenous injection of SR 33557 (0.5-10 mg/kg), 30 minutes before administration of isoproterenol, attenuated the increase in calcium content in a dose-related manner, such that 5 mg/kg SR 33557 reduced calcium overload by 50%. At this dose, SR 33557 had no effect on the number of beta-adrenergic receptors but prevented the decrease in the number of calcium channels. The total number of binding sites and the dissociation constants of each radioligand were estimated from saturation isotherms. The dissociation constants were unchanged when animals given isoproterenol or SR 33557 and isoproterenol were compared to the control group. The results indicate that SR 33557 is able to protect against the calcium overload induced by sympathetic over-stimulation. This over-stimulation of the sympathetic system causes a down-regulation of the number of active beta-adrenergic receptors and calcium channels. The down-regulation of calcium channels is selectively reduced by earlier administration of SR 33557.

Animals↗