Niguldipine, a novel dihydropyridine derivative, was tested for its effects on the cytoplasmic free Ca2+ concentration of mouse thymocytes. In quin-2-loaded cells, a concentration-dependent rise of cytoplasmic Ca2+ can be detected, which requires extracellular Ca2+. The effect of niguldipine reaches a maximum after about 5 min; a similar time course has been observed, when using concanavalin A as a stimulus. Niguldipine provokes influx of Ca2+ into thymocytes, but not of Mn2+. Moreover, the effect of niguldipine exhibits some degree of stereospecificity, since (-)-niguldipine was more effective than its (+)-enantiomer. The action of niguldipine could be reversed by addition of bovine serum albumin, but not by addition of nitrendipine. None of several agents tested (e.g. felodipine, nitrendipine, trifluoperazine, cloxacepride, phenylephrine and ouabain) could mimic the effect of niguldipine at a concentration of 1 microM.

01 Apr 1989·Agents and Actions

The effects of metoclopramide and cloxacepride on human mast cells from adenoidal tissues

Article

Author: W. Schmutzler ; Th. Greven ; U. Braam

Cloxacepride is an amide of the dopamine antagonist metoclopramide and has been reported to possess oral antiallergic properties in the rat PCA model. Both substances have now been tested in isolated mast cell preparations from human adenoidal tissues to determine whether any therapeutic antiallergic potential in man could be expected. Metoclopramide at concentrations 10(-5)-10(-3) M had no inhibitory effect but instead enhanced Con A-induced histamine release at concentrations greater than 10(-4) M. Cloxacepride at concentrations 10(-5)-10(-4) M significantly inhibited Con A-induced histamine release. This inhibitory effect was not diminished by increasing the preincubation time for up to 30 min. In contrast, cloxacepride concentrations greater than 4 x 10(-5) M caused a substantial histamine release. This effect could not be alleviated by an increase in the number of mast cells per sample. These results then suggest a very narrow range of therapeutic potential for cloxacepride.

01 Oct 1987·Cell CalciumQ2 · BIOLOGY

Calmodulin antagonism: A pharmacological approach for the inhibition of mediator release from mast cells

Q2 · BIOLOGY

Article

Author: K Gietzen ; G Metz ; G Gigl ; D Hartweg ; E Sanchez-Delgado

Several Ca2+ antagonists with either Ca2+-entry blocking or calmodulin (CaM) antagonistic properties and antiallergic drugs were investigated for their effects on mediator release from mast cells induced by different secretagogues (compound 48/80, concanavalin A, antigen-IgE and Ca2+ ionophore A23187) and for their ability to inhibit the function of CaM or phospholipid/Ca2+-dependent protein kinase (C-kinase). The effects of the different agents--with the only exception of cromolyn sodium--on histamine release elicited by compound 48/80 correlated well with their actions on two CaM-dependent enzymes whereas the activity of C-kinase was far less altered, or not altered at all. CaM antagonism of cloxacepride, picumast, oxatomide, fendiline and bepridil correlated not only with the inhibition of exocytosis evoked by compound 48/80 but also with that induced by A23187, concanavalin A and antigen-IgE. This indicates an action of these substances distal to the generation of the Ca2+ signal since the various secretagogues elevate the intracellular Ca2+ concentration by different mechanisms. However, prenylamine and thioridazine inhibited concanavalin A- and antigen-IgE-induced mediator release more potently and more effectively than that elicited by compound 48/80 or A23187. Therefore inhibition of allergic histamine release by these drugs may in part be dependent on an impairment of the Ca2+ signal. Since for each of two agents inhibition of histamine release (evoked by different releasers) parallels that of serotonin release it may be concluded that these mediators are secreted via the same mechanism. The results obtained with agents exhibiting different pharmacological properties but which share one common property, namely antagonism of CaM, strengthen the view that CaM is involved in exocytosis of mediators from mast cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	-	Merkle Pharmaceuticals	-
Asthma	Phase 2	DE	Merckle GmbH	-

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