Effect of Endothelin Receptor Antagonists on Ventricular Susceptibility in Post‐infarcted Rats

OBJECTIVES Activation of the endothelin (ET) receptor has been shown to exert an arrhythmogenic effect; however, the mechanisms remain unclear. We investigated whether ET receptor antagonists (ERAs) exert antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. METHODS Twenty‐four hours after coronary ligation, male Wistar rats received either vehicle, hydralazine, ABT‐627 (selective ETA receptor antagonist), or bosentan (nonselective ETA/ETB receptor antagonist) for 4 weeks. RESULTS Measurement of myocardial ET‐1 levels at the remote zone revealed a significant increase in vehicle‐treated rats compared with sham‐operated rats. Sympathetic reinnervation and nerve function were parallel to ET‐1 levels. Sympathetic hyperinnervation was blunted after administering either ETA or ETA/ETB blockade to a similar extent, assessed by immunohistochemical analysis of tyrosine hydroxylase, growth associated protein 43 and neurofilament, and Western blot and RT‐PCR of nerve growth factor. Dissociation between the effects of blood pressure and sympathetic innervation was noted, because ERAs and hydralazine reduced arterial pressure similarly. Arrhythmic scores during programmed stimulation in ERA‐treated rats were significantly lower than those treated with vehicle. CONCLUSIONS The ET system, especially via ETA receptors, plays an important role in the sympathetic reinnervation after infarction. Chronic use of either ETA or ETA/ETB antagonists after infarction may modify the arrhythmogenic response to electrical stimulation.