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The actions of calcium antagonists on arrhythmias and other responses to myocardial ischaemia in the rat

University of British Columbia

Studies were carried out in order to examine the actions of calcium antagonists in acute myocardial ischaemia and the mechanism(s) responsible for these actions; the scientific hypothesis under test was that calcium antagonism in the ventricles is antiarrhythmic in acute myocardial ischaemia. In addition, experiments were carried out to investigate the role of the sympathetic nervous system in arrhythmogenesis. The actions of seven calcium antagonists on responses to myocardial ischaemia were investigated in vivo using the conscious rat preparation. It was found that the drugs with identifiable actions in the heart attributable to calcium antagonism possessed antiarrhythmic activity, whereas the drugs producing only systemic vasodilatation were without tangible antiarrhythmic activity. The results were taken as evidence in support of the main hypothesis (above). In no instance did any of the drugs produce consistent dose-dependent -infarct-reducing actions. It was established from the comparison of the optical enantiomers of verapamil that antiarrhythmic potency corresponded with calcium antagonist potency. It was also shown that these drugs appeared to have no effect on g[sub Na] in the heart in vivo (as predicted from work by others, in vitro). Evidence that arrhythmias were reduced as a result of effects on i[sub si] in the ischaemic ventricle was accrued from several studies. In isolated Langendorff-perfused rat ventricles the calcium antagonist activity of the verapamil enantiomers was greatly potentiated by raising K⁺ concentration to levels seen during acute myocardial ischaemia, whereas nifedipine, which showed little if any antiarrhythmic activity in vivo did not show marked K⁺ -dependent calcium antagonist activity. In a separate series of experiments it was demonstrated that serial ablations in the CNS had profound effects on occlusion-induced arrhythmias, but that these effects occurred independently of the level of adrenoceptor activation. It was hypothesised that surgery reduced ischaemia-induced arrhythmias, by virtue of either its effects on serum K⁺ concentration or its effects on the number of circulating thrombocytes.

Text

2010-07-31

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http://hdl.handle.net/2429/27061

Pharmacology

University of British Columbia

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