INFLUENCE OF HYPOXIA ON THE MYOCARDIAL UPTAKE AND PHARMACODYNAMICS OF QUINIDINE IN ISOLATED PERFUSED RABBIT HEARTS

The effects of hypoxia on the myocardial uptake and pharmacodynamics of quinidine were studied in isolated perfused rabbit hearts. Hearts were perfused with a modified Krebs-Henseleit buffer that was equilibrated with either 95% O2-5% CO2 (normoxia) or 95% N2-5% CO2 (hypoxia). The myocardial quinidine accumulation was determined from concentration differences in aortic perfusate and coronary sinus effluent. Under hypoxic conditions, the myocardial concentration of quinidine (12.0 +/- 3.6-mu-g/g) was significantly reduced compared to normoxic conditions (24.8 +/- 8.5-mu-g/g, p < 0.01). Greater increases in QRS complex duration were observed during hypoxia (10.0 +/- 1.0 ms) compared to normoxia (7.5 +/- 1.3 ms; p < 0.05). Greater increases in MAP duration were also observed during hypoxia (64 +/- 14 ms) compared to normoxia (37 +/- 14 ms; p < 0.01). The myocardial concentration-effect relationships describing changes in QRS complex duration, QT interval, MAP duration, and ventricular effective refractory periods were linear in both groups. The curves of the concentration-effect relationships observed during hypoxia were shifed to the left compared to those observed during normoxia and the slopes of these relationships were also significantly greater (p < 0.05). These pharmacokinetic and pharmacodynamic interactions may be explained by the development of acidosis during hypoxia since the pH of the coronary sinus effluent decreased significantly during hypoxia (7.10 +/- 0.04) compared to the normoxic group (7.25 +/- 0.04, p < 0.001). Thus, although hypoxia reduces the myocardial accumulation of quinidine, greater electrophysiologic effects are observed compared to normoxic conditions. These observations likely relate to a change in responsiveness of acidotic tissue to quinidine.