Electrophysiological and antiarrhythmic actions of the kappa agonist PD 129290, and its R,R (+)-enantiomer, PD 129289

Abstract

1. The S,S (-)-enantiomer PD 129290, a kappa agonist, and its corresponding inactive R,R (+)-enantiomer (PD 129289) were studied in rat isolated hearts and in intact rats for cardiovascular and antiarrhythmic actions. The electrophysiological actions of PD 129290 were also studied in rat isolated cardiac myocytes using voltage clamp. 2. Ventricular pressure, heart rate and ECG were studied in isolated hearts while blood pressure, heart rate and ECG were studied in pentobarbitone-anaesthetized rats. In the latter, responses to electrical stimulation and coronary occlusion were also investigated. 3. In isolated hearts both enantiomers, over the concentration range 2-16 microM, dose-dependently reduced systolic ventricular pressure and heart rate while prolonging the P-R and QRS intervals of the ECG. 4. At doses of 1-32 mumol kg-1 both enantiomers reduced blood pressure and heart rate in anaesthetized rats. In addition, both enantiomers increased the size of the RSh and increased P-R, QRS, and Q-T intervals of the ECG. The thresholds for premature beats and ventricular fibrillation were dose-dependently increased by PD 129289. At lower doses PD 129290 decreased thresholds. These decreases were blocked by naloxone to reveal underlying increases similar to those seen with PD 129289. Both enantiomers increased refractory periods. 5. Naloxone (8 mumol kg-1) did not alter any of the actions of PD 129290, except to abolish the initial decreases in thresholds in intact rats seen with lower doses of PD 129290. 6. Both enantiomers (2 and 8 mumol kg-1) equally reduced arrhythmias in anaesthetized rats subject to occlusion of a coronary artery. 7. In rat isolated cardiac myocytes 20 microM PD 129290, in the presence and absence of naloxone decreased the amplitude of the transient sodium current by about 50% without affecting the voltage dependence of activation or inactivation of this current.8. The antiarrhythmic actions of both enantiomers appear to primarily result from their Class I(sodium channel blockade) properties which are independent of kappa agonism.