In vitro characterization of a novel Ca2+ entry blocker: SR 33805.
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.
Chatelain
P
P
Sanofi-Pharma Research Centre 1, Brussels, Belgium.
Clinet
M
M
Polster
P
P
Christophe
B
B
Manning
A S
AS
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007212:Indolizines / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009543:Nifedipine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007211:Indoles; D007212:Indolizines; D010627:Phenethylamines; D013450:Sulfones; C084255:SR 33805; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; C059901:fantofarone