Localization and function of ET‐1 and ET receptors in small arteries post‐myocardial infarction: Upregulation of smooth muscle ET B receptors that modulate contraction

Endothelin‐1 (ET‐1) has been implicated as a mediator of increased vascular tone during development of heart failure post‐myocardial infarction (MI). In the present study, expression and pharmacology of ET‐1 and its receptors were studied in small mesenteric arteries from rats at 5 and 12 weeks after coronary artery ligation for induction of MI, or sham‐operation. In vessels from sham‐operated and 5 week post‐MI rats preproET‐1mRNA, immunoreactive (ir) ET‐1, ET B receptor mRNA and irET B receptor were confined to the endothelium, while ET A receptor mRNA was distributed throughout the media. At 12 weeks post‐MI, preproET‐1 and irET A receptor localization was similar but ET B receptor mRNA and immunoreactivity were detectable in the media, as well as the endothelium. The ET‐1 concentration‐response curve (CRC) was progressively shifted to the right in pressurized third generation mesenteric arteries from 5 and 12 week post‐MI rats relative to sham‐operated rats, with no change in the maximum. The ET A receptor antagonist BQ‐123 (10 −6   M ) induced a rightward shift of the ET‐1 CRC in all vessels. Desensitization of ET B receptors, by exposure to SRTX S6c (3×10 −8   M ), had no effect on the ET‐1 CRC in vessels from 5 week post‐MI or sham‐op rats but induced a leftward shift in vessels from 12 week post‐MI rats. These results identify the endothelium as the primary site of ET‐1 synthesis in small arteries and the ET A receptor as mediating the effects of ET‐1 in these vessels. However, ET B receptor expression increases in vascular smooth muscle post‐MI and is linked to mechanisms that inhibit the contractile response to ET‐1.British Journal of Pharmacology (2000) 130 , 1735–1744; doi: 10.1038/sj.bjp.0703503