title: Differential time course of the vasodilator action of various calcium antagonists.
abstract: It is rather the rate of the vasodilator effect than its magnitude which determines the triggering of reflex tachycardia associated with dihydropyridine calcium antagonists (DHP-CA). We therefore compared the rate of the vasodilator effects of a series of CA (both DHP and non-DHP) in rat isolated mesenteric artery preparations (size 256 +/- 3 microns, length 2 mm) from male Wistar rats (weighing 300-350 g) in an isolated wire myograph according to Mulvany and Halpern [12]. The mean force of the KCl-induced contraction amounted to 2.3 +/- 0.1 mN/mm. Potency (given as IC50-values), differential time course of action and recovery of the contractile response of the vessels after wash-out were established. These three parameters adhere to the following sequences: (1. potency) barnidipine [corrected] > (S)-lercanidipine > barnidipine racemate [corrected]> amlodipine > nifedipine, lacidipine > (R)-lercanidipine > verapamil, mibefradil; (2. differential time course) lacidipine, amlodipine > (S)- and (R)-lercanidipine, barnidipine [corrected], barnidipine racemate [corrected] > mibefradil, verapamil, nifedipine; (3. recovery) nifedipine > verapamil, barnidipine [corrected], amlodipine > barnidipine, lacidipine > mibefradil, (R)-lercanidipine > (S)-lercanidipine. In conclusion, barnidipine [corrected] proved to be the most potent vasodilator agent; interestingly, barnidipine was 20 times less potent when applied as a racemic mixture. A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia. For non-DHP (verapamil, mibefradil) reflex tachycardia probably is prevented by a direct effect on the conductive tissue in the myocardium.
authors.affiliation: Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van der Lee
authors.forename: K L
authors.initials: KL
authors.lastname: Kam
authors.forename: M
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: P A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries; D020748:Mibefradil; D051381:Rats; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D014665:Vasodilator Agents; D017311:Amlodipine; D020748:Mibefradil