Lack of calcium-antagonist effects of PCA-4230, a novel 1,4-dihydropyridine derivative on several animal isolated tissues

Villarroya, Mércedes; López, Manuela G.; Cillero, F. J.; Sunkel, Carlos; Priego, Julián

doi:10.1016/0014-2999(90)94355-2

Cited by 1 publication

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PCA‐4230 is a drug belonging to a series of 1,4‐dihy‐dropyridines that lack the aryl substituent in position 4 of the dihydropyridine ring (Sunkel et al , 1988). Because of this modification, PCA‐4230 does not exhibit the typical vasodilator and relaxant effects on vascular smooth muscle (Villarroya et al , 1990). In addition, PCA‐4230 showed a K i value 500 fold higher than that of nitrendipine in studies performed to measure the affinity of both drugs for the L‐type Ca channel (Villarroya et al , 1990).…”

Section: Discussionmentioning

confidence: 99%

“…Because of this modification, PCA‐4230 does not exhibit the typical vasodilator and relaxant effects on vascular smooth muscle (Villarroya et al , 1990). In addition, PCA‐4230 showed a K i value 500 fold higher than that of nitrendipine in studies performed to measure the affinity of both drugs for the L‐type Ca channel (Villarroya et al , 1990). Therefore, our data would support the idea of a mechanism that is not completely due to blockade of L‐type Ca channels in the antiproliferative effects of dihy‐dropyridines.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antiproliferative effects of PCA‐4230, a new antithrombotic drug, in vascular smooth muscle cells

Río¹,

Sunkel²,

Larcher

et al. 1997

British J Pharmacology

View full text Add to dashboard Cite

1 In the present study we examined the e ects of PCA-4230, a novel antithrombotic agent, on the growth of cultured A10 vascular smooth muscle cells (rat aorta). 2 The action of PCA-4230 on cell proliferation and on serum-induced DNA synthesis was determined by measuring the cell number and the incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), respectively. 3 PCA-4230 reversibly inhibited vascular smooth muscle cell proliferation. The increase in cell number was signi®cantly reduced in the presence of 1 and 50 mM PCA-4230. 4 DNA synthesis was concentration-dependently inhibited by PCA-4230 (0.5 to 50 mM) in A10 cells that were synchronized by 48 h serum starvation and then re-stimulated by serum repletion, with an IC 50 value of 13 mM. However, serum-induced DNA synthesis in bovine aortic endothelial cells was not signi®cantly a ected by PCA-4230. In addition, PCA-4230 (50 mM) caused a signi®cant drop in PDGF-BB-mediated BrdU incorporation in A10 cells.5 The e ect of PCA-4230 on serum-induced DNA synthesis was compared to that elicited by nifedipine, another dihydropyridine-class inhibitor of vascular smooth muscle proliferation. PCA-4230 (10 mM) elicited a degree of inhibition similar to that of nifedipine at equimolar concentration. 6 To de®ne the nature of the cell proliferation inhibition, an evaluation of cell cycle progression was undertaken. Flow cytometry studies of DNA content in synchronized cells revealed a block of the seruminducible cell cycle progression. This inhibitory e ect was markedly reduced when PCA-4230 was added 2 h after serum repletion. 6 Accordingly, PCA-4230 (50 mM) caused a 95 and 90% decrease in the elevation of c-fos and c-jun proto-oncogenes expression as evaluated by Northern blot analysis of mRNA induced early after serum addition. 7 The present results indicate that PCA-4230 inhibits vascular smooth muscle cell proliferation, in culture, by altering the cell cycle progression. Flow cytometric studies of DNA content and the down regulation of c-fos and c-jun proto-oncogenes, suggest that the drug is acting at the early G 0 /G 1 transition phase. PCA-4230 may hold promising potential for the prevention of structural abnormalities of blood vessels associated with atherosclerosis and vascular diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%