Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic rats

被引：13

作者：

Briede, J ^{[1
]}

Stivrina, M ^{[1
]}

Stoldere, D ^{[1
]}

Bisenieks, E ^{[1
]}

Uldrikis, J ^{[1
]}

Poikans, J ^{[1
]}

Makarova, N ^{[1
]}

Duburs, G ^{[1
]}

机构：

[1] Latvian Inst Organ Synth, LV-1006 Riga, Latvia

来源：

CELL BIOCHEMISTRY AND FUNCTION | 2004年 / 22卷 / 04期

关键词：

1,4-dihydropyridine derivatives; Ca2+ channel antagonists; cerebrocrast; etaftoron; niludipine; nicardipine; nimodipine; glucose homeostasis; normal and STZ-induced diabetic rats;

D O I：

10.1002/cbf.1091

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Analysis of the effect of several 1,4-DHP Ca2+ channel antagonists on experimental and clinical diabetes shows that structurally similar Ca2+ channel antagonists can exert opposite effects on Ca2+ influx, glucose homeostasis and insulin secretion. The influence of the Ca2+ channel antagonists on pancreatic beta cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNARES protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure-function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF2 group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5 mg kg(-1), p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats. Copyright (C) 2004 John Wiley Sons, Ltd.

引用

页码：219 / 224

页数：6

共 46 条

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