IN-VITRO CHARACTERIZATION OF A NOVEL CA-2- SR33805( ENTRY BLOCKER )

In this study, SR 33805 was shown to inhibit competitively [H-3]fantof arone binding to cardiac sarcolemmal membranes. In contrast, SR 33805 was shown to inhibit allosterically [H-3](+)-PN200-110, [H-3](-)-D888 and cis-(+)-[H-3]diltiazem binding. In isolated rabbit atrial preparat ions, SR 33805 was shown to be the least potent of fantofarone, nifedi pine, verapamil and diltiazem in terms of both negative chronotropic a nd inotropic responses (IC50's, 6 and 12 muM, respectively). In superf used rat aortic strips, SR 33805 like other Ca2+ channel antagonists, caused a significant inhibition of both K+-induced Ca-45(2+) influx an d contractile responses. In addition this agent was shown to antagoniz e Ca2+-induced contractions in K+-depolarized aorta with a pA2 value o f 8.39 +/- 0.02. In femoral, renal and basilar arteries, SR 33805 was equiactive to the other Ca2+ channel antagonists studied in antagonizi ng K+-induced contractions (IC50 approximately 40 nM), but unlike the reference Ca2+ channel antagonists, was equiactive in antagonizing ser otonin-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 vascula r smooth muscle and devoid of any potent negative inotropic actions.