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The cardiovascular and antiarrhythmic actions of a series of kappa opioid agonists and related compounds

University of British Columbia

The cardiovascular and antiarrhythmic actions of the kappa (K) opioid receptor agonists are not well characterized. This may be the result of the limited role opioids play in the regulation of cardiovascular function and the fact that pharmaceutical companies concentrate on their analgesic properties. The studies described in this thesis attempt to characterize the cardiovascular and antiarrhythmic properties of a novel series of arylacetamide k receptor agonists and related compounds. The compounds examined included U-62,066E (spiradoline), U-50,488H, (-)PD129,290 and its inactive enantiomer, (+)PD129,289, (±)PD117,302 and its inactive enantiomer, (+)PD123,497. Studies were conducted to determine whether the K receptor is involved in the antiarrhythmic actions of these compounds and if it is not, attempt to determine a mechanism by which these compounds may confer antiarrhythmic protection against both electrically-induced and ischaemic arrhythmias. Studies were therefore conducted in rats in the absence and presence of the opioid antagonists, naloxone and Mr2266 or, when possible, with inactive enantiomers of k receptor agonists. Six novel compounds sharing the arylacetamide structure were examined for their actions on haemodynamic and EGG actions in intact pentobarbitone-anaesthetised rats. The previously unpublished parts of the thesis focuses on U-62,066E (spiradoline) and also provides results obtained in isolated cardiac myocytes for (±)PD117,302 and its inactive enantiomer, (+)PD123,497. Previously published data contained in the appendices covers the other three compounds. All compounds produced similar actions. All the compounds examined produced a dose-dependent reduction in heart rate, blood pressure, and prolonged the P-R, QRS duration, and Q-aT intervals with an accompanying increase in RSh (a measure of sodium channel block in the rat). The effects of the arylacetamides, exemplified by spiradoline, were assessed using a modified Langendorff isolated heart preparation. Spiradoline and related compounds reduced the sinus beating rate and contractility of hearts in a concentration-dependent manner. ECG effects in isolated hearts included prolongation of the P-R interval and QRS width. The effects of the compounds on the ability of electrical stimulation to stimulate the heart were examined in pentobarbitone-anaesthetised rats. Spiradoline and related compounds dose-dependently increased the current and duration of stimulus required to stimulate the heart and also increased ventricular fibrillation threshold. All compounds prolonged effective refractory period and reduced maximum following frequency. In an attempt to determine effectiveness against ischaemic arrhythmias in rats after coronary occlusion a dose of 2.5 μmol/kg/min spiradoline was given in the absence and presence of 2.5 μmol/kg/min naloxone. Spiradoline reduced the incidence of VT from 100% in controls to 33 and 44% in the absence and presence of naloxone. The incidence of VF was reduced from 100% to 22% and 0% in the absence and presence of naloxone. All chemically related arylacetamides were similarly antiarrhythmic. In order to delineate a mechanism by which these compounds may be antiarrhythmic their effects on sodium and potassium currents were examined in isolated rat cardiac myocytes. Spiradoline blocked these currents in a concentration-dependent and reversible manner. The EC₅₀ for half-maximal sodium current block was 66μM. Spiradoline also produced a hyperpolarizing shift in the voltage-dependence of inactivation of the channel but did not alter activation kinetics. The block produced by spiradoline on sodium channels was both tonic and use-dependent. Additional studies with (±)PD117,302 and its inactive enantiomer, (+)PD123,497 showed that the block produced by these arylacetamides is pH-dependent and that block is consistent with activity at an extracellular site on the sodium channel. These results indicate that spiradoline and the arylacetamides examined produce antiarrhythmic actions independent of the K receptor in the rat. Our results demonstrate the sodium channel, and to a lesser extent, potassium channels blocking actions of these compounds.

Thesis/Dissertation

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2009-04-27

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http://hdl.handle.net/2429/7599

Pharmacology and Therapeutics

University of British Columbia

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