SR 33557, a novel calcium entry blocker. I. In vitro isolated tissue studies.
The effects of SR 33557 on isolated cardiovascular preparations were compared to those of nifedipine, verapamil and diltiazem. In rat aortic strips, SR 33557, like nifedipine, verapamil and diltiazem, caused a significant and simultaneous inhibition of potassium-induced 45Ca++ influx and contractile responses (nifedipine greater than SR 33557 greater than verapamil greater than diltiazem). SR 33557 also antagonized Ca(++)-induced contractions in K(+)-depolarized aorta preparations (pA2:9.08 +/- 0.03) and is the first calcium channel antagonist, structurally not related to 1,4-dihydropyridines, to inhibit competitively contractions induced by BAY K8644. In spike-generating vascular smooth muscle (rat portal vein), contractures evoked by noradrenaline (4 microM) or KCl (100 mM) were reduced by all four antagonists, the pharmacological potency being nifedipine greater than SR 33557 greater than verapamil greater than diltiazem. Unlike SR 33557, nifedipine, verapamil and diltiazem showed a parallel enhancement of frequency of spontaneous contractions in rat portal vein in spite of a concentration-related reduction in amplitude. By using rabbit atrial preparations, spontaneous right atrial rate and electrically stimulated (120/min) basal contractions of left atria were used as indices of chronotropy and inotropy. The potency series for negative chronotropic effects was nifedipine greater than SR 33557 greater than verapamil greater than diltiazem. For negative inotropic effects the potency order was verapamil greater than nifedipine greater than SR 33557 greater than diltiazem, respectively. Thus, SR 33557 should depress heart rate to a greater extent than ventricular contractility. These results suggest that SR 33557 is a potent calcium entry blocker that (unlike verapamil and diltiazem) is particularly selective for vascular smooth muscle and devoid of any potent negative inotropic actions.
Sanofi-Labaz Research Center, Brussels, Belgium.
P
P
Polster
B
B
Christophe
M
M
Van Damme
A
A
Houlliche
P
P
Chatelain
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007212:Indolizines / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D007212:Indolizines; D010627:Phenethylamines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C059901:fantofarone; D011188:Potassium; D002118:Calcium