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Evaluation of Endothelin-1–Induced Pulmonary Vasoconstriction Following Myocardial Infarction

Research Center, Montreal Heart Institute, and the Department of Medicine, University of Montreal, Montreal, Quebec, Canada, H1T 1C8

To whom requests for reprints should be addressed at ¹ Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada H1T 1C8. Email: Jocelyn.dupuis{at}bellnet.ca

Abstract

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 sarafo-toxin 6c (S6c) were performed. Response to ET was also assessed in the presence of ET-R antagonists. Heterodimeriza-tion 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 µM 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.

Key Words: myocardial infarction • heart failure • receptor • lung • pulmonary hypertension • endothelin • endothelium • pharmacology

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