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 (3x10(-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.
Gray
G A
GA
Endothelial Cell Biology and Molecular Cardiology Section, Centre for Cardiovascular Science, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EX8 9XD. gillian.gray@ed.ac.uk
Mickley
E J
EJ
Webb
D J
DJ
McEwan
P E
PE
D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D016232:Endothelins / Q000097:blood; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011498:Protein Precursors / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics* / Q000502:physiology; D016019:Survival Analysis; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D011498:Protein Precursors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; D011189:Potassium Chloride; C072247:cyclo(Trp-Asp-Pro-Val-Leu)