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The antiarrhythmic activity of ±-opioid agonist RSD 939 is unrelated to ±-agonism

University of British Columbia

Cumulating evidence have indicated that various opioid agonists and antagonists, especially kappa (ic) agonists, can exhibit a variety of cardiovascular and antiarrhythmic actions. Two important questions arise. First, are these cardiovascular and antiarrhythmic actions mediated by the opioid receptors? Second, what is the underlying mechanism of actions if these effects are not mediated by opioid receptors? Previous studies have shown that some of the cardiac and cardiovascular actions of ic agonists are a result of direct actions on cardiac ionic channels and are independent of ic agonism. RSD 939 is structurally related to ic agonists and in binding studies appears to be a potent and selective ic agonist. The present study is an attempt to study the involvement of opioid-receptors in the cardiovascular and antiarrhythmic activity of ic agonists and to determine the underlying mechanism of such activities using RSD 939. The cardiovascular and antiarrhythmic actions of RSD 939 were investigated in a series of studies. Firstly, the initial profile of acute cardiovascular and toxic actions of RSD 939 were investigated. RSD 939 was given as cumulative i.v. bolus doses to anaesthetised rats whose blood pressure, heart rate and ECG were measured. It was found that at 8 jimole/kg, RSD 939 decreased both blood pressure and heart rate by 25%. At 5 tmole/kg, it also prolonged the P-R interval and increased RSh of the ECG. However, at a higher dose of 16 jtmole/kg, it also produced changes in the Q-T interval. Since opioid receptors are found in the vagus nerve, in several sympathetic ganglia as well as the heart, opioid peptides can influence the cardiovascular system both centrally and peripherally. Therefore, in order to determine the direct cardiac effects of RSD 939, it is necessary to examine the drug effects in the absence of neuronal and humoral influence on hearts. In isolated rat hearts, over the concentration range 0.1 to 3.0 riM, RSD 939 concentration-dependently prolonged the P-R and QRS intervals of the ECG. The antiarrhythmic activity of RSD 939 was determined in terms of its ability to prevent both electrically-induced and ischaemia-induced arrhythmias. For electrical stimulation, two silver electrodes were implanted into the rat’s left ventricle and the ability of the drug to raise the ventricular fibrillation threshold (VFt) was determined. In the ischaemia model, the left anterior decending coronary artery (LAD) of the rat was ligated. Occlusion of the LAD results in the production of acute myocardial ischaemia and ventricular arrhythmias in a predictable and reproducible manner that mimics conditions found clinically in myocardial ischaemia and infarction. At a dose of 1.5 jtmole/kg/min, RSD 939 significantly increased the threshold voltage needed to induce ventricular fibrillo-flutter. At the same dose, the incidence of ventricular arrhythmias produced by occlusion was also significantly reduced (reduction of arrhythmia score from 7.0 in control groups to 3.2 in RSD 939 group). Naloxone at a dose which had no cardiovascular or ECG actions, but blocked opioid receptors, was used to differentiate between opioid and nonopioid receptor-mediated actions of RSD 939. In a random and double-blind manner, either control vehicle or 8 j.imole/kg(1 tM in vitro) naloxone was given to rats or infused into isolated rat hearts. RSD 939 or control vehicle was administered 5 mm later. The cardiovascular and antiarrhythmic actions of RSD 939 in naloxone pre-treated preparations and untreated rats were also compared. It was found that the ECG and antiarrhythmic effects of RSD 939 were not antagonized by naloxone. The antiarrhythmic action of naloxone alone was also evaluated and compared in the two groups. Naloxone alone had no effect on any of the ECG variables except for P-R interval which was prolonged slightly. However, naloxone alone reduced the incidence and severity of ischaemia-induced arrhythmia. This action of naloxone was not synergistic with RSD 939 since no difference in antiarrhythmic potency was found between the naloxone pre-treated and nonnaloxone pre-treated groups. From the above observations, it can be concluded that the cardiac and cardiovascular actions of RSD 939 were not mediated through opioid receptors. Effects of RSD 939 on the ECG parameters such as P-R, QRS, RSh and Q-T intervals and electrical stimulation parameters such as threshold current (iT), threshold duration (tT), and effective refractory period (ERP) were used to establish the underlying mechanism of actions of its antiarrhythmic activities. RSD 939 dose-dependently prolonged P-R, QRS, RSIi, iT, and tT without significant effects on Q-T and ERP until higher doses. Since most sodium channels blockers will increase P-R, QRS, RSh, iT, and tT and most potassium channel blockers will prolong Q-T and ERP, we concluded that RSD 939 mediated its cardiac and cardiovascular effects by direct cardiac sodium and potassium channel blockade.

Thesis/Dissertation

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2009-02-26

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http://hdl.handle.net/2429/5201

Pharmacology

University of British Columbia

UBCV

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