Submitted on September 29, 2007
Accepted on February 11, 2008
Effect of Endothelin Receptor Antagonists on Ventricular Susceptibility in Post-infarcted Rats
Tsung-Ming Lee1, Chien-Chang Chen2, Mei-Shu Lin3, and Nen-Chung Chang4*
1 Department of Medicine, Taipei Medical University and Chi-Mei Medical Center, Taiwan - Republic of China
2 Department of Surgery, Chi-Mei Medical Center, Taiwan - Republic of China
3 Department of Pharmacy, National Taiwan University and Hospital, Taiwan - Republic of China
4 Department of Medicine, Taipei Medical University and Hospital, Taiwan - Republic of China
* To whom correspondence should be addressed. E-mail: ncchang{at}tmu.edu.tw.
This study investigated whether selective endothelin (ET) ETA or nonselective ETA/ETB receptor blockade exerted antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats received either vehicle, ABT-627 (selective ETA receptor antagonist), bosentan (nonselective ETA/ETB receptor antagonist), or hydralazine for 4 weeks. Measurement of myocardial ET-1 levels at the remote zone revealed a significant increase in vehicle-treated infarcted rats compared with sham-operated rats, consistent with increased activities of ET-1 after infarction. Sympathetic nerve function changes assessed by the norepinephrine content of myocardium and the dialysate and plasma dihydroxyphenylglycol levels were parallel to ET-1 levels. Immunohistochemical analysis for tyrosine hydroxylase, growth associated protein 43 and neurofilament also confirmed the change of nerve function. This was accompanied with a significant upregulation of nerve growth factor protein expression and mRNA in the vehicle-treated infarcted rats, which reduced after administering either ETA or ETA/ETB blockade to a similar extent. The beneficial effects of ET receptor antagonists on sympathetic nerve function and structures were dissociated from their blood pressure-lowering effect because ET receptor antagonists and hydralazine reduced arterial pressure similarly. Arrhythmic severity during programmed stimulation in ET receptor antagonists-treated rats was significantly lower than that in vehicle-treated infarcted rats. Our data indicate that the ET system, especially via ETA receptors, plays an important role in attenuating sympathetic reinnervation after infarction. Independent of their hemodynamic effects, chronic use of either ETA or ETA/ETB antagonists may modify the arrhythmogenic response to programmed electrical stimulation.
