Influence of Perfusion Flow Rate on Uptake and Pharmacodynamics of Quinidine in Isolated Perfused Rat Heart

Abstract

With the single-pass isolated perfused rat heart preparation, we examined the effect of perfusate flow rate on the time course of quinidine output concentration (Cout) and the change in the QT interval (delta QT) on the electrocardiogram. Four hearts were perfused at 5.6 mL/min with quinidine (20 microM) for 25-45 min. This was followed by a 50-min washout period with drug-free perfusate. This procedure was repeated four times in each heart. Using a one-compartment model, the rate constants calculated from the time course of Cout (k) and delta QT (Ke) were similar (p > 0.05) and did not vary among the five phases. A zero-time intercept for Cout indicated shunting of perfusate (1.2-13.6%), from which the coronary output concentration (Ccor) and coronary flow rate were calculated. These experiments were repeated in another six hearts, except flow rates of 2, 4, 6, 8, and 2 mL/min were used in each phase. Equilibration of Cout and delta QT was faster with increasing flow rate, and ke and k were similar at each flow rate (p > 0.05). A modified Kety-Renkin-Crone equation was fitted to values for k and coronary flow rate. The mean permeability surface product estimate was 15.3 +/- 3.0 mL/min/g heart, which in comparison with the highest flow rate used (9 mL/min/g heart) suggests that quinidine has intermediate permeability. The excellent fit obtained indicates that a more complex model, incorporating heterogeneous flows or opening of capillaries at higher flows, was not necessary.(ABSTRACT TRUNCATED AT 250 WORDS)