Haemodynamic, electrocardiographic, electrophysiologic and pharmacokinetic activity of 4'-hydroxypropranolol in dogs

We determined the haemodynamic, electrocardiographic and electrophysiologic effects, and the pharmacokinetic properties of 4′-hydroxypropranolol (4′-OHP) by conducting three different experiments in dogs. In experiment 1 the plasma concentrations of 4′-OHP (mg/kg, i.v.) in pentobarbital anaesthetized dogs were determined by HPLC and pharmacokinetic parameter values were estimated. The terminal elimination half-life (t1/2) for 4′-OHP was 69.4 min, the apparent volume of distribution (V_d) was 3.39 L/kg and the total clearance (Cl_t) was 53.6 mL/min·kg. These data were subsequently used to calculate the loading and maintenance doses of 4′-OHP required to produce targeted steady-state plasma concentrations for 4′-OHP of 30, 60, 120, 240 and 480 ng/mL. In experiment 2 the haemodynamic and electrocardiographic effects for target plasma concentrations of 4′-OHP were determined in two groups of pentobarbital anaesthetized dogs, and beta-blocking activity was assessed by infusion or bolus doses of isoproterenol. The haemodynamic and electrocardiographic effects of the target plasma concentrations (30, 60, 120 ng/mL) of 4′-OHP were first determined in seven pentobarbital anaesthetized dogs (Group 1). Beta blocking activity was assessed by the infusion of 0.1 μg/kg/min isoproterenol. The infusion of 4′-OHP produced dose dependent decreases in heart rate, cardiac output, dP/dt_max, mean arterial pressure and left ventricular diastolic pressure. The PR interval of the lead II electrocardiogram increased and the QT_c interval decreased. These haemodynamic and electrocardiographic changes became apparent at plasma 4′-OHP concentrations equal to or greater than 30 ng/mL. Plasma concentrations of 4′-OHP equal to or greater than 30 ng/mL prevented the haemodynamic and electrocardiographic effects of isoproterenol infusion. In group 2 dogs, (seven dogs) the haemodynamic and electrocardiographic effects of target plasma concentrations (30, 60, 120, 240, 480 ng/mL) of 4′-OHP were evaluated and beta-blocking activity was assessed by the i.v. bolus administration of 1 and 4 μg/kg of isoproterenol. The infusion of 4′-OHP produced haemodynamic and electrocardiographic changes similar to those in group 1 dogs. In addition, the QRS duration of the electrocardiogram increased at plasma concentrations of 4′-OHP equal to or greater than 240 ng/mL. The haemodynamic and electrocardiographic effects of i.v. bolus dose administrations of 1 and 4 μg/kg isoproterenol were abolished by plasma concentrations of 4′-OHP equal to or greater than 240 ng/mL. In experiment 3 we determined the electrophysiologic effects of 10^?9 to 10^?5 mmol/L 4′-OHP on Tyrodes superfused bundles of canine Purkinje fibres. Action potential duration and the effective refractory period decreased at superfusate concentrations of 4′-OHP equal to or greater than 10^?7 mmol/L. Action potential overshoot, action potential total amplitude, the rate of rise of phase O (dV/dt) and spontaneous rate decreased at superfusage concentrations of 4′-OHP equal to or greater than 800 ng/mL. These studies demonstrate that: 1) 4′-OHP produces haemodynamic, electrocardiographic and electrophysiologic effects similar to those of other beta-blocking drugs in pentobarbital anaesthetized dogs; 2) the haemodynamic and electrocardiographic effects produced by 4′-OHP are