Involvement of calcium channels in fibroblast growth factor-induced activation of arterial cells in spontaneously hypertensive rats.
To gain insight into the mechanisms that could account for the abnormal vascular structure in spontaneously hypertensive rats (SHR) and to determine whether this could be affected by calcium channel blockers, we compared the influence of dihydropyridines on basic fibroblast growth factor (bFGF)-induced DNA synthesis in cultured adventitial fibroblasts isolated from SHR and Wistar-Kyoto rat (WKY) aorta. Our results showed that (a) bFGF was a potent mitogen for adventitial fibroblasts, much more active in SHR-derived than in WKY-derived cells, thus confirming the hyperreactivity of the SHR arterial cells; (b) the mitogenic potency of bFGF could be reduced by dihydropyridines (rank order of potency was nifedipine approximately nisoldipine > nitrendipine > nimodipine); and (c) the nifedipine inhibitory effect could be completely and partially antagonized in WKY- and SHR-derived fibroblasts, respectively, by the calcium channel agonist Bay K 8644. Moreover, the extent of nifedipine inhibitory extent increased and decreased in SHR- and WKY-derived fibroblasts, respectively, according to duration of treatment of cells with the drug, suggesting that SHR fibroblasts became progressively more sensitive whereas those of WKY became more refractory to the drug treatment. These data indicate that in aortic fibroblasts stimulated by bFGF, L-type calcium channels participate in the antimitotic effect of dihydropyridines and suggest the existence of interactions between these channels and the bFGF signaling pathways. They also suggest that nifedipine inhibits bFGF-induced DNA synthesis by different mechanisms in SHR and WKY fibroblasts.
Zhu
D L
DL
CNRS URA 1482, Laboratoire de Pharmacologie, Faculté de Médecine Necker, Paris, France.
Hérembert
T
T
Caruelle
D
D
Caruelle
J P
JP
Marche
P
P
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013936:Thymidine / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008934:Mitogens; D016222:Fibroblast Growth Factor 2; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004247:DNA; D013936:Thymidine