Falipamil

The chronotropic cardiac effects of falipamil were studied in conscious dogs with chronic atrioventricular (AV) block. Falipamil (0.5-2 mg/kg) initially increased atrial rate dose dependently. After atropine and atropine-pindolol, falipamil (2 mg/kg) decreased atrial rate, but after pindolol, it did not modify atrial rate. After atropine-pindolol-phenoxybenzamine, atropine-pindolol-yohimbine, atropine-pindolol-verapamil, and atropine-pindolol-quinidine pretreatment, falipamil produced atrial bradycardia. Falipamil dose-relatedly decreased ventricular rate. Falipamil (2 mg/kg) decreased ventricular rate after atropine, pindolol, and atropine-pindolol more than under basal conditions. After the other four pretreatments, it also produced ventricular bradycardia. Falipamil did not affect mean blood pressure (MBP) at any dose. These results (a) show that the initial atrial cardio-acceleration produced by falipamil results from its direct vagolytic action; (b) show that absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate; (c) suggest that the falipamil ventricular bradycardia is partly buffered by the vagolytic effect, norepinephrine (NE) release, and involvement of alpha 2-adrenoceptors; (d) exclude involvement of postsynaptic muscarinic, alpha- and beta-adrenoceptors, and of the slow calcium current in the mechanism(s) by which falipamil decreases cardiac automaticity; and (e) suggest possible involvement of a quinidine-sensitive current in this (these) mechanism(s).

The pharmacodynamic interaction between dihydropyridine calcium antagonists and several cationic amphiphilic agents with respect to their negative inotropic action has been studied in isolated guinea-pig left atria. (+/-)-Bepridil (CAS 64706-54-3), (+/-)-cis-diltiazem (CAS 33286-22-5), falipamil (CAS 77862-92-1), (+/-)-gallopamil (CAS 16662-47-2), lidocaine (CAS 6108-05-0), procainamide (CAS 614-39-1), or quinidine (CAS 50-54-4) were added at fixed concentrations. Afterwards, concentration-response curves for nifedipine (CAS 21829-25-4), the S-enantiomer niguldipine.HCl and its R-enantiomer dexniguldipine.HCl (CAS 113165-32-5), (+/-)-nimodipine (CAS 66085-59-4) (+/-)-nitrendipine (CAS 39562-70-4), or (+/-)-isradipine (CAS 75695-93-1) were obtained. In most cases, a left-ward shift in the concentration-response curve of the dihydropyridine was observed. The extent of this shift varied between dihydropyridines, and it depended on the catamphiphilic compound present. A high correlation was found between the different dihydropyridines, when comparing the extent of displacement of their concentration-response curves by the various catamphiphilic test compounds. Although quantitative differences exist between the different dihydropyridines, they are affected in potency by other compounds with a rather similar pattern. Accordingly, some general predictions about the interactions of a given dihydropyridine might be possible using limited datasets.