Effects of manidipine and nitrendipine enantiomers on the plateau phase ofK+-induced intracellular Ca2+ increase in GH(3) cells

Citation
M. Cataldi et al., Effects of manidipine and nitrendipine enantiomers on the plateau phase ofK+-induced intracellular Ca2+ increase in GH(3) cells, EUR J PHARM, 376(1-2), 1999, pp. 169-178
Citations number
24
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN journal
0014-2999 → ACNP
Volume
376
Issue
1-2
Year of publication
1999
Pages
169 - 178
Database
ISI
SICI code
0014-2999(19990702)376:1-2<169:EOMANE>2.0.ZU;2-A
Abstract
The aim of the present study was to investigate whether the chirality and t ype of substitution at position 3 of the dihydropyridine ring influences th e pattern of voltage-gated Ca2+ channel blockade. For this purpose, the eff ect of R- and S-enantiomers of manidipine and nitrendipine, separated by ch iral High-Pressure-Liquid-Chromatography columns, were investigated by fura -2 microfluorimetry during the plateau phase of the intracellular Ca2+ ([Ca 2+](i)) increase induced by 55 mM K+ and by patch-clamp recording of Ca2+ c hannel activity in GH(3) cells. R- and S-enantiomers of both nitrendipine a nd manidipine produced a [Ca2+](i) decay of the K+-induced plateau phase th at followed a biexponential pattern with a 'fast' and a 'slow' phase. The S -configuration of both nitrendipine and manidipine produced a larger [Ca2+] (i) decrease during the 'fast phase', and a faster and smaller [Ca2+](i) de crease in the 'slow phase' than did the R-enantiomers. The S- and R-enantio mers of manidipine, which possess a longer and more lipophilic side chain a t position 3 of the dihydropyridine ring, induced a slower [Ca2+](i) decrea se than that observed with the respective nitrendipine enantiomers. Accordi ngly, patch-clamp experiments revealed that the S-enantiomers of both dihyd ropyridines displayed a faster onset of action and produced a greater block ade than the R-enantiomers. These results suggest that the enantiomeric con figuration and a small side chain at position 3 of the dihydropyridine ring are factors in the chemical structure which influence the pattern of block ade of voltage-sensitive Ca2+ channels. (C) 1999 Elsevier Science B.V. All rights reserved.