SR 33805 oxalate

Smooth muscle cell cycle and proliferation. Relationship between calcium influx and sarco-endoplasmic reticulum Ca2+ATPase regulation.[Pubmed:8910375]

J Biol Chem. 1996 Nov 1;271(44):27788-94.

The role of Ca2+ influx in the regulation of the sarco-endoplasmic reticulum Ca2+ATPases (SERCA) associated with intracellular Ca2+ pools was investigated during smooth muscle cell (SMC) proliferation induced by platelet-derived growth factor (PDGF). We first defined that the previously described up-regulation of the SERCA2a isoform found in vascular SMC after a 24-h stimulation with PDGF (Magnier, C. , Papp, B., Corvazier, E., Bredoux, R., Wuytack, F., Eggermont, F., Maclouf, J., and Enouf, J. (1992) J. Biol. Chem. 267, 15808-15815) was precisely associated with SMC entry into S phase as it appeared linked with [3H]thymidine incorporation. This was further confirmed by testing the effect of transforming growth factor-beta1, which inhibited both aortic SMC proliferation associated with G1 cell cycle arrest and PDGF-induced SERCA2a up-stimulation. Then, we tested the role of Ca2+ influx by using SR 33805, a new Ca2+ channel blocker, which was characterized with regard to the voltage Ca2+ channel blocker nifedipine and the capacitative entry Ca2+ blocker SKF 96365. SR 33805 was found to be the most potent inhibitor of both PDGF-induced SMC proliferation and the associated rise in intracellular Ca2+ concentration with IC50 values of 0.2 +/- 0.1 and 0.31 +/- 0. 04 microM, respectively. Finally, by examining in parallel both SERCA2a and SERCA2b isoforms, in terms of activity and expression, we could determine that PDGF-induced stimulation of total SERCA activity (detected by formation of the phosphorylated intermediate, E approximately P) and of SERCA2a expression (Western blotting) were abolished when extracellular Ca2+ entry was prevented by SR 33805. This study demonstrates that SERCA2a up-regulation is: 1) related to the G1/S transition step of cell cycle and 2) dependent on Ca2+ entry during PDGF-induced SMC proliferation.

Effects of a new class of calcium antagonists, SR33557 (fantofarone) and SR33805, on neuronal voltage-activated Ca++ channels.[Pubmed:7996445]

J Pharmacol Exp Ther. 1994 Dec;271(3):1348-52.

SR33557 (fantofarone) and SR33805 are structurally novel calcium antagonists that bind selectively to the alpha 1-subunit of the L-type Ca++ channel at a site distinct from the classical 1,4-dihydrophyridine, phenylalkylamine and benzothiazepine sites but in allosteric interactions with them. Blocking effects of fantofarone and SR33805 on the different types of voltage-activated Ca++ currents have been investigated with the whole-cell patch-clamp method in chick dorsal root ganglion neurons (for T-, L- and N-type currents) and in rat cerebellar Purkinje neurons (for P-type current) in primary culture. Neuronal L-type Ca++ channels are blocked totally by fantofarone and SR33805 in the microM range of concentration as in skeletal muscle and cardiac cells at a holding membrane potential of -80 mV. The sequence of efficacy is SR33805 (IC50 = 26 nM) > fantofarone (IC50 = 0.35 microM). N- and P-type channels are not very sensitive to fanto-farone and SR33805 (IC50 approximately 5 microM). The T-type channel is not affected by these drugs.

In vitro characterization of a novel Ca2+ entry blocker: SR 33805.[Pubmed:8223943]

Eur J Pharmacol. 1993 Aug 15;246(3):181-93.

In this study, SR 33805 was shown to inhibit competitively [3H]fantofarone binding to cardiac sarcolemmal membranes. In contrast, SR 33805 was shown to inhibit allosterically [3H](+)-PN200-110, [3H](-)-D888 and cis-(+)-[3H]diltiazem binding. In isolated rabbit atrial preparations, SR 33805 was shown to be the least potent of fantofarone, nifedipine, verapamil and diltiazem in terms of both negative chronotropic and inotropic responses (IC50's 6 and 12 microM, respectively). In superfused rat aortic strips, SR 33805 like other Ca2+ channel antagonists, caused a significant inhibition of both K(+)-induced 45Ca2+ influx and contractile responses. In addition this agent was shown to antagonize Ca(2+)-induced contractions in K(+)-depolarized aorta with a pA2, value of 8.39 +/- 0.02. In femoral, renal and basilar arteries, SR 33805 was equiactive to the other Ca2+ channel antagonists studied in antagonizing K(+)-induced contractions (IC50 approximately 40 nM), but unlike the reference Ca2+ channel antagonists, was equiactive in antagonizing serotonin-induced contractions (IC50 approximately 250 nM). This suggests that the effects of SR 33805 depend mainly on membrane potential. In conclusion, SR 33805 is a potent Ca2+ channel antagonist which, unlike fantofarone, verapamil and diltiazem, is highly selective for vascular smooth muscle and devoid of any potent negative inotropic actions.