Influence of dietary fat on the pharmacodynamics of propafenone in isolated, perfused rabbit hearts.

BACKGROUND: The fatty acid composition of the phospholipids in sarcolemma may significantly influence cell membrane functions. We evaluated the effects of dietary fat on the pharmacodynamics of the antiarrhythmic drug propafenone in isolated, perfused rabbit hearts. METHODS AND RESULTS: Three groups of weanling rabbits (n = 9 each group) were fed diets of 10% wt/wt lard, fish oil, or safflower oil for 40 days. Differences in electrophysiological variables were assessed at baseline and during propafenone perfusion. Myocardial concentration-effect relations were determined by plotting electrophysiological effects versus coronary sinus propafenone concentrations. The linoleic acid content of isolated sarcolemma was higher in the safflower group (33.4 +/- 11.4%) than in the lard (13.4 +/- 2.3%, p less than 0.01) and fish oil (8.5 +/- 1.4%, p less than 0.01) groups, whereas the omega-3 fatty acid content was higher in the fish oil group (p less than 0.01). During propafenone perfusion, greater changes in ventricular conduction time were observed in the lard group (22 +/- 11 msec) than in the safflower oil group (10 +/- 7 msec, p less than 0.05), whereas changes in ventricular conduction time in the fish oil group (16 +/- 7 msec) were intermediate between the lard and safflower oil groups. The slopes of the linear myocardial concentration-effect relations describing changes in QRS duration were steeper in the lard group (0.22 +/- 0.07 msec/micrograms/ml) than in the safflower oil group (0.13 +/- 0.04 msec/micrograms/ml, p less than 0.01) but not in the fish oil group (0.17 +/- 0.08 msec/microgram/ml, p = NS). Strength-interval curves were similar at baseline in all three groups. During propafenone perfusion, the threshold current was increased significantly at long coupling intervals (250-380 msec) in the lard group (1.8 +/- 1.0 mA) compared with the safflower oil group (0.8 +/- 0.6 mA, p less than 0.05) but not compared with the fish oil group (1.2 +/- 0.6 mA, p = NS). CONCLUSIONS: Dietary fat significantly alters the fatty acid composition of the phospholipids in sarcolemma. Propafenone effects on ventricular conduction time and ventricular excitability are significantly influenced by the type of dietary fat.

Propafenone disposition and pharmacodynamics in normal and norepinephrine-induced cardiomyopathic rabbit hearts.

The myocardial disposition and pharmacodynamics of propafenone were studied in 10 normal and 10 norepinephrine-induced cardiomyopathic rabbit hearts. The left ventricular propafenone concentrations measured after perfusion of propafenone (0.3 microM) for 150 min were similar in the normal group (18 +/- 8 micrograms/g) compared to the cardiomyopathy group (20 +/- 5 micrograms/g, P = NS). However, the concentration of propafenone in cardiomyopathic left ventricular papillary muscle, which was always extensively involved in the inflammatory process, was significantly lower (11 +/- 2 micrograms/g) compared to normal papillary muscle (19 +/- 4 micrograms/g, P less than .05). During propafenone perfusion a significantly greater increment in ventricular conduction time was observed in the cardiomyopathy group (17 +/- 6 msec) compared to the normal group (12 +/- 3 msec, P less than .05). The propafenone myocardial concentration-effect relationships describing changes in QRS duration were shifted to the left in the cardiomyopathy group. Furthermore, the slopes of these linear concentration-effect relationships were greater in the cardiomyopathy group (1.80 +/- 0.60 msec/micrograms/g) compared to the normal group (1.07 +/- 0.25 msec/micrograms/g, P less than .01). The ventricular effective refractory period was shorter at base line in the cardiomyopathy hearts (156 +/- 21 msec) compared to the normal group (176 +/- 23 msec, P less than .08). However, propafenone effects on changes in the ventricular effective refractory period were similar in the two groups. Thus, the myocardial accumulation of propafenone is reduced in areas of extensive necrosis observed in norepinephrine-induced cardiomyopathy. As well, cardiomyopathic tissue is more responsive to propafenone effects on ventricular conduction time.

Myocardial uptake and pharmacodynamics of quinidine and propafenone in isolated rabbit hearts: metabolic versus respiratory acidosis.

The influence of metabolic and respiratory acidosis on the myocardial accumulation and pharmacodynamics of quinidine and propafenone was studied in isolated perfused rabbit hearts. Three pH groups were evaluated: physiologic buffer, pH 7.4; metabolic acidosis, pH 7.0; and respiratory acidosis, pH 7.0. Myocardial accumulation of quinidine and propafenone was significantly reduced during acidosis. Although myocardial quinidine concentrations were similar in the metabolic acidosis group (14.4 +/- 1.2 micrograms/g) and the respiratory acidosis group (14.5 +/- 1.3 micrograms/g), the myocardial propafenone concentration was significantly less during metabolic acidosis (8.9 +/- 2.0 micrograms/g) as compared with respiratory acidosis (12.7 +/- 2.4 micrograms/g, p less than 0.05). The myocardial concentration-effect relationships were linear over the observed myocardial concentration ranges. The slopes of the linear concentration-effect relationships describing QRS duration were increased twofold by both types of acidosis as compared with normal pH (p less than 0.05). In contrast, the slopes of the concentration-effect relationships describing changes in ventricular repolarization and refractoriness were increased only during metabolic acidosis as compared with pH 7.4 (p less than 0.05). Thus, for any given concentration of drugs, the effects of quinidine and propafenone on ventricular conduction time are dependent on the pH of the perfusate, whereas these drug effects on ventricular repolarization and refractoriness are dependent on the buffer composition.

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 micrograms/g) was significantly reduced compared to normoxic conditions (24.8 +/- 8.5 micrograms/g, p less than 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 less than 0.05). Greater increases in MAP duration were also observed during hypoxia (64 +/- 14 ms) compared to normoxia (37 +/- 14 ms; p less than 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 shifted to the left compared to those observed during normoxia and the slopes of these relationships were also significantly greater (p less than 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 less than 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.

Tissue levels and some in vivo responses to a monofluorinated analogue of amphetamine in the mouse.

The metabolism and some behavioral properties of each of the optical isomers of 2-amino-1-fluoro-3-phenylpropane hydrochloride (fluoroamphetamine, FAM) were examined and compared to those of the optical isomers of amphetamine (AM). Substitution of fluorine into the side-chain of AM increased the rate of elimination of drug from brain and modified the kinetics from a one- to a two-compartment model. Urinary excretion of unchanged S-(-)-FAM was reduced from that observed after R-(-)-AM, suggesting a more extensive metabolism. Fluorine substitution also modified the behavioral response to AM. Thus, each optical isomer of FAM produced paradoxical reductions in locomotor activity and body temperature.

Reserpine-induced hypothermia and its reversal by dopamine agonists.

Prior treatments with reserpine altered the thermic response of mice to subsequently administered apomorphine and amphetamine. Thus, normal mice exhibited hypo- and hyper-thermic responses to apomorphine and (+)-amphetamine, respectively but did not respond to (-)-amphetamine. These responses were each readily attenuated by haloperidol. Reserpinized mice, on the other hand, exhibited hyperthermic responses to all three agonists and these responses were not attenuated by haloperidol. In addition to its hypothermic action, reserpine also produced hypoactivity which was reversed by (+)-amphetamine. This reversal of hypoactivity was attenuated by haloperidol. These data suggest that reversal of reserpine-induced hypothermia by dopamine agonists results through activation of mechanisms which are separate from those normally associated with agonist-induced thermic responses. Reversal of hypoactivity, on the other hand, appears to be due to reactivation of those systems which normally regulate locomotor activity.