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

Abstract

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 (Vd) was 3.39 L/kg and the total clearance (Clt) 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 microgram/kg/min isoproterenol. The infusion of 4'-OHP produced dose dependent decreases in heart rate, cardiac output, dP/dtmax, mean arterial pressure and left ventricular diastolic pressure. The PR interval of the lead II electrocardiogram increased and the QTc 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 micrograms/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 micrograms/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 0 (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 apparent at relatively low plasma concentrations (30 ng/mL); 3) the concentrations of 4'-OHP that are required to produce direct cardiac electrophysiologic effects are unlikely to be responsible for clinical antiarrhythmic activity and 4) 4'-OHP blocks the haemodynamic and electrocardiographic effects of infusions and i.v. bolus administration of isoproterenol.