Evaluation of endothelin-1-induced pulmonary vasoconstriction following myocardial infarction.
Endothelin (ET) levels are elevated in congestive heart failure secondary to myocardial infarction (MI) and correlate well with the severity of pulmonary hypertension (PH), suggesting that the ET peptide could contribute to the pathophysiology of venous PH. Alterations of pulmonary vasoreactivity to ET after MI and the respective roles of the ET(A) and ET(B) receptors (ET(A)-R and ET(B)-R) have never been evaluated, to our knowledge. MI was induced in rats. Three weeks later, small pulmonary resistance arteries were mounted on a microvascular myograph. Cumulative concentration-response curves to ET-1 and sarafotoxin 6c (S6c) were performed. Response to ET was also assessed in the presence of ET-R antagonists. Heterodimerization of receptors was evaluated by immunoprecipitation of the ET(B)-R, followed by western blotting for the expression of the ET(A)-R. Maximal vasoconstriction and sensitivity to ET-1 were similar in sham and MI with values of 88 +/- 3.9% and 80 +/- 3.8%, respectively. The response to S6c was similarly less in both sham (67 +/- 5.7%) and MI groups (60 +/- 6.6%). When administered alone, the ET(A)-R antagonist (10 nM A-147627.1) and the ET(B)-R antagonist (1 microM A-192621.1) had no significant effect. However, their combination markedly reduced vaso-constriction (52 +/- 5.3%; P < 0.001). The endothelial and medial distribution of ET-Rs was similar in sham and MI groups. In vitro studies demonstrated co-immunoprecipitation of the ET(A)-R and ET(B)-R. Vasoconstriction of isolated resistance pulmonary arteries to ET agonists is not altered after MI. Dual antagonism results in optimal blockade of vasoconstriction, possibly because the ET(A)-R and ET(B)-R can form functional heterodimers.
Sauvageau
Stéphanie
S
Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada H1T 1C8.
Thorin
Eric
E
Caron
Alexandre
A
Dupuis
Jocelyn
J
D000818:Animals; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects*; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000819:agonists / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014757:Viper Venoms / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C057354:sarafotoxins s6