ELECTROPHYSIOLOGICAL AND ANTIARRHYTHMIC ACTIONS OF THE KAPPA-AGONIST PD-129290, AND ITS R,R (-ENANTIOMER, PD-129289())

1 The S,S (-)-enantiomer PD 129290, a K agonist, and its corresponding inactive R,R (+)-enantiomer (PD 129289) were studied in rat isolated hearts and in intact rats for cardiovascular and antiarrhythmic action s. The electrophysiological actions of PD 129290 were also studied in rat isolated cardiac myocytes using voltage clamp. 2 Ventricular press ure, heart rate and ECG were studied in isolated hearts while blood pr essure, heart rate and ECG were studied in pentobarbitone-anaesthetize d rats. In the latter, responses to electrical stimulation and coronar y occlusion were also investigated. 3 In isolated hearts both enantiom ers, over the concentration range 2-16 muM, dose-dependently reduced s ystolic ventricular pressure and heart rate while prolonging the P-R a nd QRS intervals of the ECG. 4 At doses of 1-32 mumol kg-1 both enanti omers 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 decrea ses were blocked by naloxone to reveal underlying increases similar to those seen with PD 129289. Both enantiomers increased refractory peri ods. 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 intac t 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 muM PD 129290, in the presence and absence of naloxone decreased t he amplitude of the transient sodium current by about 50% without affe cting the voltage-dependence of activation or inactivation of this cur rent. 8 The antiarrhythmic actions of both enantiomers appear to prima rily result from their Class I (sodium channel blockade) properties wh ich are independent of kappa agonism.