Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.     

Preselection Thymocytes Are More Sensitive to T Cell Receptor Stimulation Than Mature T Cells

During T cell development, thymocytes which are tolerant to self-peptides but reactive to foreign peptides are selected. The current model for thymocyte selection proposes that self-peptide–major histocompatibility complex (MHC) complexes that bind the T cell receptor with low affinity will promote positive selection while those with high affinity will result in negative selection. Upon thymocyte maturation, such low affinity self-peptide–MHC ligands no longer provoke a response, but foreign peptides can incidentally be high affinity ligands and can therefore stimulate T cells. For this model to work, thymocytes must be more sensitive to ligand than mature T cells. Contrary to this expectation, several groups have shown that thymocytes are less responsive than mature T cells to anti-T cell receptor for antigen (TCR)/CD3 mAb stimulation. Additionally, the lower TCR levels on thymocytes, compared with T cells, would potentially correlate with decreased thymocyte sensitivity. Here we compared preselection thymocytes and mature T cells for early activation events in response to peptide–MHC ligands. Remarkably, the preselection thymocytes were more responsive than mature T cells when stimulated with low affinity peptide variants, while both populations responded equally well to the antigenic peptide. This directly demonstrates the increased sensitivity of thymocytes compared with T cells for TCR engagement by peptide–MHC complexes.     

EFFECTS OF STROPHANTHIDIN ON THE SLOW INWARD CURRENT IN GUINEA-PIG ISOLATED VENTRICULAR MYOCYTES

1. The effect of strophanthidin on the slow inward current (Isi) and on contractile force were studied in guinea-pig isolated ventricular myocytes and intact papillary muscles, respectively. In myocytes, both low (10 nmol/L) and high (1-10 mumols/L) concentrations had small or no effects in either direction on Isi whereas norepinephrine (10-100 nmol/L) increased it. To determine whether the same results are obtained after decreasing or increasing intracellular calcium or sodium, the same concentrations of strophanthidin were tested in different procedures that are known to (i) increase [Ca]i and decrease [Na]i (high [Ca]o, 3.6-5.4 mmol/L; low [Na]o, 112 mmol/L; (ii) decrease [Ca]i and increase [Na]i (low [Ca]o, 0.45-1 mmol/L; Sr, 1 mmol/L; (iii) decrease [Ca]i and [Na]i (Cd, 0.1-0.2 mmol/L); and (iv) increase [Ca]i and [Na]i (veratridine, 0.2 mumol/L). High [Ca]o and veratridine increased whereas low [Ca]o and Cd decreased Isi. In contrast, during these various procedures, strophanthidin had small and inconsistent effects at a low or high concentration. In intact papillary muscles, low strophanthidin decreased whereas high strophanthidin increased contractile force. It is concluded that strophanthidin has little direct or indirect effect on Isi and that the decrease in force by low and increase in force by high concentrations in intact muscle are probably related to demonstrated decrease and increase, respectively, in intracellular sodium activity.     

Comparative inotropic effect of calcium, endothelin-1, and forskolin on ferret papillary muscles during acidosis

Summary— Acidosis affects multiple steps in the excitation-contraction coupling pathway of myocardium, producing decreased calcium sensitivity of myofibrils and modification of the function of the sarcoplasmic reticulum. Our aim was to evaluate the effectiveness of three different classes of inotropic agents under acidotic conditions: 1) forskolin, an adenylate cyclase activator that enhances cellular cyclic AMP concentrations, 2) elevated extracellular Ca²⁺ and 3) endothelin-1, an activator of the inositol triphosphate, diacylglycerol pathway. Ferret papillary muscles were mounted in organ baths containing normal physiological solution (pH = 7.4). After baseline tension was measured, the muscles were bathed in an acidotic solution (pH = 6.98) that decreased tension to 40% of the control; subsequently, the muscles were washed with normal physiological solution until they returned to baseline. Each inotropic agent was added to the bathing solution in a concentration sufficient to increase tension by 40% above the baseline. Then the solution was made acidotic (pH = 6.98) in the continuous presence of that concentration of inotropic agent and the resultant steady-state developed tension measured. The increases in tension induced by each inotropic agent at normal pH were adjusted to be similar; in contrast, the response to each drug in acidosis was significantly different. Under acidotic conditions, endothelin-1 was the most effective inotropic agent in restoring the depressed developed tension. This was possibly due to enhancement of the myofilament sensitivity to Ca²⁺, which was more effective than increasing [Ca²⁺]_i through elevating extracellular Ca²⁺ or the addition of forskolin which increased [Ca²⁺]_i but desensitized the myofilaments to Ca²⁺.     

硫氮(艹卓)酮对心肌钙反常损伤的影响

本实验建立心肌钙反常损伤模型,观察钙通道阻滞剂硫氮(艹卓)酮对心肌钙反常损伤的影响。发现硫氮(艹卓)酮能显著减轻心肌挛缩,提高冠脉流量和冠脉流出液中超氧化物歧化酶(SOD)活性,降低心肌细胞内的 CPK 释放及心室肌组织钙含量。实验结果表明,硫氮(艹卓)酮对心肌钙反常损伤有明显的保护作用。     

Effects of calcium in continuous cardioplegia on myocardial protection

The effects of calcium (Ca) on a hyperkalemic cardioplegic solution for continuous cardioplegia were examined in an isolated perfused working rat heart model. The coronary arteries were perfused with a modified Krebs-Henseleit bicarbonate buffer (K-H) solution, containing various concentrations of Ca(0.1, 0.6, 1.2, and 2.5 mmol/l) and a high concentration of potassium (20 mmol/l), for 180 min, after which cardiac arrest was induced at 37°C for 180 min. Cardiac function and creatine kinase (CK) were measured. In the control group, K-H solution was infused in place of the cardioplegic solution, and cardiac arrest was not induced. No significant differences were observed between the groups infused with the K-H solution containing Ca concentrations of 0.6, 1.2, and 2.5 mmol/l in the percent recovery of aortic flow (82.1±2.9%, 80.6±2.0%, and 71.5±3.7% (mean±SEM) respectively) or in the recovery of other indices of cardiac function, or in CK leakage. There were also no significant differences in the recovery of cardiac function and CK leakage between these groups and the control group. In the Ca 0.1 mmol/l group, however, the characteristic Ca paradox was observed. These findings suggest that if the Ca concentration in a cardioplegic solution is higher than 0.6 mmol/l during continuous cardioplegia, excellent cardioprotective effects will be achieved.     

The depressing effect of tetracaine and ryanodine on the slow outward current correlated with that of contraction in voltage-clamped frog muscle fibres

The effects of tetracaine (10–50 M) and ryanodine (0.1–10 M) were tested on the slow outward K⁺ current (I _so) and the mechanical tension of isolated frog muscle fibres in a voltage-clamp device (double mannitol-gap) connected to a mechanoelectric transducer. In the concentration range tested, both drugs induced a simultaneous inhibition of tension and current. In all cases the effect on tension was twice that on current. The tetracaine-induced current and tension blocks were fully reversible and dose-dependent. In contrast the ryanodine effects on current and tension were not reversible and did not exhibit a dose dependence except for the delay before the onset of the response, which was shortened when the concentration was raised. Linear regression analysis of the time-dependent and dose-dependent effects of both drugs indicated a strong correlation between the decreases in tension and current. It is concluded that the slow outward current is partly under the control of the Ca²⁺ release from sarcoplasmic reticulum during contraction.     

[3H]5-HT binding in post-mortem human cerebral cortex: methodological considerations

Summary The effects of different membrane preparations and assay conditions on [³H]5-HT binding to post-mortem human cortical tissue was studied. Optimal binding necessitated thorough removal of endogenous 5-HT and this was achieved either by hypotonic lysis or by preincubation of the membranes at 37C. Calcium chloride (4 mM) increased specific [³H]5-HT binding. The further addition of ascorbic acid (5.7 mM) or ascorbic acid and clorgyline (10 M) reduced specific [³H]5-HT binding.     

Differential Calcium Binding Protein Immunoreactivity Distinguishes Classes of Relay Neurons in Monkey Thalamic Nuclei

The distributions of neurons displaying immunoreactivity for two calcium binding proteins, parvalbumin and 28Kd calbindin, were studied in the thalamus of M. fascicularis. Colocalization experiments were carried out to determine the extent to which parvalbumin- and calbindin-like immunoreactivity was found in the same cells and the extent to which either was localized in GABAergic interneurons. Anterograde and retrograde tracing experiments involving the fluorescent tracer, fast blue, were also used to determine that cells expressing the calcium binding proteins projected upon the cerebral cortex. In the dorsal thalamus, nuclei are distinguished by different patterns of parvalbumin-like and calbindin-like immunoreactivity. In certain nuclei, for example the lateral dorsal and anterior pulvinar, neurons express immunoreactivity for only one of the calcium binding proteins. In others, neurons in different layers, for example the dorsal lateral geniculate nucleus, or in different compartments, for example the intralaminar nuclei, express immunoreactivity for either parvalbumin or calbindin; in other nuclei, for example the ventral group, neurons are mixed and immunoreactivity for parvalbumin and calbindin is commonly colocalized. In the ventral thalamus and epithalamus, similar patterns are observed. Colocalization of parvalbumin- and GABA-immunoreactivity is found in all cells of the reticular nucleus but only in certain cells in selected nuclei of the dorsal thalamus, namely the dorsal lateral geniculate and magnocellular medial geniculate. No calbindin-positive cells are also GABA-positive. Most parvalbumin and/or calbindin positive cells in the dorsal thalamus project to the cerebral cortex, as indicated by the retrograde tracing studies, and many parvalbumin positive fibres entering the cerebral cortex could also be shown to contain fast blue anterogradely transported from a thalamic injection. Most of the major sensory and motor pathways entering the dorsal thalamus express parvalbumin immunoreactivity. The optic tract also expresses calbindin immunoreactivity but most other calbindin positive fibres entering the thalamus ascend in the midbrain tegmentum. The differential distributions of parvalbumin and calbindin implied by these results suggest that thalamic cells belonging to different functional systems and projecting differentially upon the cerebral cortex can be distinguished by differential expression of these or closely related calcium binding proteins. This may yield clues to their differential responsivity to afferent driving.     

Effect of papaverine on tone and contractions of the depolarized smooth muscle of the guinea pig taenia coli

Experiments were carried out on isolated strips of guinea pig taenia coli. The smooth muscle was depolarized in a solution with high potassium concentration (120 mM KCl). The effect of papaverine (in concentrations of 10^–5 to 3.10^–5 g/ml) on the tone and off-response to a prolonged and strong hyperpolarizing current was investigated on the denervated muscle. Papaverine was found: 1) to abolish contractile responses to application of histamine, bradykinin, and acetylcholine; 2) to reduce the tone of the depolarized muscle and abolish the effect of an increase in the Ca⁺⁺ concentration in the external medium on muscle tone; 3) to have no effect on the amplitude and velocity of the ascending phase of the off-response; 4) to accelerate the descending phase of the off-response. The following hypotheses are put forward to explain the result: 1) in the cell membrane there are chemically excitable calcium channels which are blocked by papaverine; 2) in the membrane there are calcium leakage channels responsible for the maintenance of tone and blocked by papaverine; 3) papaverine has negligible effect on electrically excitable calcium channels.A. V. Vishnevskii Institute of Surgery, Academy of Medical Sciences of the USSR, Moscow. Bio-Inorganic Chemicals BIKhS Research Institute, Kupavna, Moscow Region. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Fedorov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 85, No. 2, pp. 177–180, February, 1978.