Cataldi M, Taglialatela M, Palagiano F, Secondo A, de Caprariis P, Amoroso S, di Renzo G, Annunziato L
Department of Neuroscience, School of Medicine, University of Naples Federico II, Italy.
Eur J Pharmacol. 1999 Jul 2;376(1-2):169-78. doi: 10.1016/s0014-2999(99)00149-1.
The aim of the present study was to investigate whether the chirality and type of substitution at position 3 of the dihydropyridine ring influences the pattern of voltage-gated Ca2+ channel blockade. For this purpose, the effect of R- and S-enantiomers of manidipine and nitrendipine, separated by chiral High-Pressure-Liquid-Chromatography columns, were investigated by fura-2 microfluorimetry during the plateau phase of the intracellular Ca2+ ([Ca2+]i) increase induced by 55 mM K+ and by patch-clamp recording of Ca2+ channel activity in GH3 cells. R- and S-enantiomers of both nitrendipine and manidipine produced a [Ca2+]i decay of the K+-induced plateau phase that 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 decrease in the 'slow phase' than did the R-enantiomers. The S- and R-enantiomers of manidipine, which possess a longer and more lipophilic side chain at position 3 of the dihydropyridine ring, induced a slower [Ca2+]i decrease than that observed with the respective nitrendipine enantiomers. Accordingly, patch-clamp experiments revealed that the S-enantiomers of both dihydropyridines displayed a faster onset of action and produced a greater blockade than the R-enantiomers. These results suggest that the enantiomeric configuration and a small side chain at position 3 of the dihydropyridine ring are factors in the chemical structure which influence the pattern of blockade of voltage-sensitive Ca2+ channels.
