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

1. 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. 2. 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. 3. 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. 4. 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