ABSTRACT
AM 92016 (1-(4-methanesulphonamidophenoxy)- 3-(N-methyl-3-4-dichlorophenethylamino)-2-propanol benzoic acid salt), an oxypropanolamine analogue of sotalol, has been shown to possess Class III anti-arrhythmic properties in-vitro at concentrations showing 1000 times more potency than sotalol. The aim of this study was to characterize the effects of AM 92016 in-vivo. When administered to anaesthetized guinea-pigs, AM 92016 (10 micrograms kg-1 -5 mg kg-1) significantly increased heart rate, systolic arterial blood pressure, left ventricular systolic pressure and the contractile index dp dtmax. AM 92016 also significantly decreased the QT interval of the electrocardiogram from 135 +/- 10 to 105 +/- 4 ms (5 mg kg-1). The time to onset of the first arrhythmia and ventricular fibrillation, induced by intravenous infusion of ouabain, was shortened in the presence of AM 92016. Ouabain-induced ventricular fibrillation occurred at 18 +/- 5 and 12 +/- 3 min (P < 0.05) in control and AM 92016-(1 mg kg-1) treated guinea-pigs, respectively. An infusion of AM 92016 (2.5 micrograms kg-1 min-1) to anaesthetized pigs significantly increased the total number of arrhythmias occurring following coronary artery occlusion from 266 +/- 26 in control pigs to 535 +/- 148 (P < 0.05) in those receiving AM 92016. The time to onset of ventricular fibrillation was also significantly reduced in anaesthetized pigs from 24 +/- 1 to 18 +/- 3 min in the presence of AM 92016. The drug did not change haemodynamics in the anaesthetized pig. We conclude that AM 92016 exhibited proarrhythmic rather than antiarrhythmic activity when administered in-vivo to either guinea-pigs or pigs.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Hemodynamics/drug effects , Sotalol/analogs & derivatives , Anesthesia, Inhalation , Animals , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/prevention & control , Blood Pressure/drug effects , Guinea Pigs , Heart Rate/drug effects , Male , Myocardial Contraction/drug effects , Myocardial Ischemia/physiopathology , Ouabain , Sotalol/pharmacology , Swine , Ventricular Fibrillation/physiopathologyABSTRACT
1. The aim of this study was to compare the abilities of diltiazem and siratiazem to inhibit concentration-response curves for contractile responses to calcium in arterial and intestinal smooth muscle and cardiac muscle. 2. Diltiazem and siratiazem inhibited, in a concentration-dependent manner, the maximum contraction produced by cumulative addition of calcium chloride to rabbit mesenteric artery, ileum and paced atria in vitro. The order of potency, as indicated by the IC25 values (with 95% confidence intervals) for siratiazem was ileum, 0.33 microM (0-0.63) > mesenteric artery, 0.75 microM (0.32-1.01) and for diltiazem was ileum 0.1 microM (0.007-0.14) = mesenteric artery 0.13 microM (0-0.22). 3. In rabbit atria, the IC25 was of the order of 10 microM for both siratiazem and diltiazem. 4. Both drugs also inhibited calcium concentration-response curves in sheep cerebral arteries and in this tissue the IC25 values were 1.18 (0.37-1.63) and 0.89 (0-1.36) microM for siratiazem and diltiazem, respectively. 5. It is concluded that siratiazem, like diltiazem, blocks entry of calcium via voltage-operated channels with a similar potency to diltiazem on rabbit ileum and cardiac muscle and sheep cerebral arteries but is less potent on rabbit mesenteric arteries.
