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Prevention of ischemia-induced arrhythmias in the rat : a comparative study of ester-linked RSD compounds with their amide-linked analogues Wang, Wei-Qun

Abstract

These studies were intended to investigate the in vivo cardiac electrophysiological and antiarrhythmic activities of a related series of RSD compounds, which included ester-linked compounds (RSD973, RSD1009, RSD1046) and their amide-linked analogues (RSD996, RSD997, RSD1044). Special emphasis was placed on a comparison of their selectivity for myocardial ischemia-induced arrhythmias. The regional ischemia model used was ligation of a branch of left coronary artery in anesthetized rats. Antiarrhythmic activity was expressed as effects on incidence, severity and duration of ventricular arrhythmias, including premature ventricular beats (PVBs), ventricular tachycardia (VT) and ventricular fibrillation (VF). A dose-response curve for antiarrhythmic activity was constructed by plotting the percent change in arrhythmia score, from control value, versus log-m dose. The effective dose producing 50% protection (ED₅₀) was calculated from the dose-response curves. The results showed that all compounds studied were protective against ischemiainduced arrhythmias in a dose-dependent manner. At sufficiently high doses, these compounds completely abolished VT or VF and markedly reduced PVB. The mortality caused by sustained VT or VF was also significantly reduced. There were no obvious similarities in antiarrhythmic effectiveness among the different pairs of ester and amide compounds with respect to antiarrhythmic dose-response curves. However, antiarrhythmic dose-response curve analyses showed that esters RSD973 and RSD1009 had antiarrhythmic effectiveness similar to that of their corresponding amide analogues RSD996 and RSD997, respectively, in terms of efficacy, potency and curve slope. The antiarrhythmic dose-response curve for the ester RSD1046 was parallel to that for its amide analogue RSD1044 with a right shift (i.e. lower potency). The results suggested that the underlying mechanisms for the antiarrhymic effects of esters and corresponding amide analogues might be the same, although the exact mechanisms remain unclear. The effects of ester and amide analogues on haemodynamic and electrocardiographic (ECG) parameters in the absence of myocardial ischemia were investigated. In addition, electrical stimulation was applied to the heart to examine drug effects on cardiac tissue excitability and refractoriness. Cumulative dose-response curves were constructed and the potencies were expressed as D₂₅values (i.e. effective dose producing 25% change from predrug value). Both ester and amide compounds decreased blood pressure (BP) and heart rate (HR) in a dose-dependent manner. The ester-linked compounds were less potent for effects on blood pressure and heart rate than their amide-linked analogues. In most cases, a maximal response (efficacy) could not be obtained while the slopes of dose-response curves did not differ between ester and amide analogues. According to their effects on the ECG and electrical stimulation variables, the compounds could possess both sodium (Na⁺) and potassium (K⁺) channel blocking activities. Prolongation of PR and QRS intervals of ECG, and increase in iT and VF-VTt of electrical stimulation were considered to be mainly attributable to Na⁺ channel blockade, while prolongation of QT interval, increase in ERP and decrease in MFF to be mainly attributable to K⁺ channel blockade. RSD compounds influenced most of these indicators in a dose-dependent fashion. Ester analogues appeared to be less potent for the effects on indicators than their corresponding amide analogues, although it was not possible to establish this conclusion statistically for all the different indicators. Comparison (by ratios) of potencies for indicators of Na+ channel blockade (PR, iT) to those for indicators of K⁺ channel blockade (QT, ERP) suggested no preference for Na+ or K⁺ blockade between ester and amide analogues. Finally, in order to evaluate selectivity for antiarrhythmic effects on arrhythmias induced by myocardial ischemia, therapeutic indices were estimated from the ratio of D25 values for BP, HR, ECG and electrical stimulation to the ED5 0 for antiarrhythmic activity. The morpholino esters RSD973 and RSD1009 had higher therapeutic indices, especially for those indices related to the ECG, than their amide analogues RSD996 and RSD997. However, for the corresponding dimethoxy pair, RSD1046 failed to show higher therapeutic indices than its amide analogue RSD1044, due to its lower potencies for both antiarrhythmic activity as well as electrophysiological effects on normal cardiac tissue. Such results suggest that the ester or amide group on morpholino compounds might be involved in the selectivity for myocardial ischemia-induced arrhythmias through interaction with other molecular moieties. The tentative suggestion drawn from this study, that ester-linked compounds with certain molecular structures provide wider safety margin with less haemodynamic depression, less bradycardiac effect and less potential proarrhythmic activity than their amide-linked analogues, needs to be confirmed in a larger series (at least twice the size of the present series) of structurally complementary compounds. The underlying mechanisms of action of the esters and amides remain to be elucidated.

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