Effect of endothelin receptor antagonists on ventricular susceptibility in postinfarcted rats.
This study investigated whether selective endothelin (ET) type A (ET(A)) or nonselective ET(A)/ET(B) 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 ET(A) receptor antagonist), bosentan (nonselective ET(A)/ET(B) receptor antagonist), or hydralazine for 4 wk. The 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 the administration of either ET(A) or ET(A)/ET(B) 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 ET(A) receptors, plays an important role in attenuating sympathetic reinnervation after infarction. Independent of their hemodynamic effects, a chronic use of either ET(A) or ET(A)/ET(B) antagonists may modify the arrhythmogenic response to programmed electrical stimulation.
Lee
Tsung-Ming
TM
Dept. of Medicine, Taipei Medical University, Taipei, Taiwan.
Chen
Chien-Chang
CC
Lin
Mei-Shu
MS
Chang
Nen-Chung
NC
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000077868:Atrasentan; D015153:Blotting, Western; D000077300:Bosentan; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D019922:GAP-43 Protein; D016900:Neurofilament Proteins; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D006830:Hydralazine; D008734:Methoxyhydroxyphenylglycol; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D000077300:Bosentan; C010117:3,4-dihydroxyphenylglycol; D000077868:Atrasentan; D009638:Norepinephrine