Effects of manidipine and nitrendipine enantiomers on the plateau phase of K+-induced intracellular Ca2+ increase in GH3 cells.
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.
Cataldi
M
M
Department of Neuroscience, School of Medicine, University of Naples Federico II, Italy.
Taglialatela
M
M
Palagiano
F
F
Secondo
A
A
de Caprariis
P
P
Amoroso
S
S
di Renzo
G
G
Annunziato
L
L
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology; D002460:Cell Line; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D005456:Fluorescent Dyes; D005470:Fluorometry; D016257:Fura-2; D007424:Intracellular Fluid / Q000378:metabolism; D009568:Nitrendipine / Q000737:chemistry / Q000494:pharmacology*; D009578:Nitrobenzenes; D018408:Patch-Clamp Techniques; D010879:Piperazines; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D009578:Nitrobenzenes; D010879:Piperazines; C054218:manidipine; D009568:Nitrendipine; D011188:Potassium; D002118:Calcium; D016257:Fura-2