Localization and function of ET-1 and ET receptors in small arteries post-myocardial infarction:: Upregulation of smooth muscle ETB 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-lmRNA, immunoreactive (ir) ET-1, ETB receptor mRNA and irET(B) receptor were confined to the endothelium, while ETA receptor mRNA was distributed throughout the media. At 12 weeks post-MI, preproET-1 and irET(A) receptor localization was similar but ETB 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 ETA receptor antagonist BQ-123 (10(-6) M) induced a rightward shift of the ET-1 CRC in all vessels. Desensitization of ETB receptors, by exposure to SRTX S6c (3 x 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 ETB receptor as mediating the effects of ET-1 in these vessels. However, ETB receptor expression increases in vascular smooth muscle post-MI and is linked to mechanisms that inhibit the contractile response to ET-1.