Different endothelin receptors involved in endothelin-1- and sarafotoxin S6B-induced contractions of the human isolated coronary artery.
1. Endothelin receptors, that mediate contraction of the human isolated coronary artery, were characterized by use of a number of agonists and antagonists. Contraction induced by the non-selective agonists, endothelin (ET)-1 and sarafotoxin S6b, was compared in endothelium-intact and endothelium-denuded ring segments. The effects of ET-1 and BQ-123 (an ETA receptor antagonist) were investigated both in ring segments and in spirally cut strips. Lastly, the effect of phosphoramidon was studied on contraction induced by big-ET-1. 2. The order of agonist potency (pD2) in endothelium-intact coronary artery ring segments was: ET-1 (8.27) approximately sarafotoxin S6b (8.16) > big-ET-1 (< 7.1) approximately ET-3 (< 6.9). [Ala1,3,11,15]ET-1 (ETB receptor agonist) caused significant contraction only at 1 microM, whereas 0.3 microM big-ET-3 had no effect. Removal of the endothelium in ring segments did not affect the contractile response to ET-1 or to sarafotoxin S6b. 3. After a full concentration-response curve had been obtained to ET-1 or sarafotoxin S6b, further contractions of the endothelium-intact coronary artery segments could only be achieved by applying ET-1 in segments exposed to sarafotoxin S6b, and not the reverse. 4. BQ-123 (0.1 microM) antagonized contractions of endothelium-intact ring segments induced by sarafotoxin S6b (pKB 7.86). Only 10 microM BQ-123 antagonized contractions induced by ET-1 (pKB 5.75). FR139317 was also more potent against sarafotoxin S6b (pKB 8.24-8.47) than against ET-1 (pKB 6.11). [Ala1,3,11,15]ET-1 (1 microM) had no effect on the contractile response to ET-1 or to sarafotoxin S6b. 5. In strip preparations with intact endothelium, the pD2 of ET-l increased to 9.04 =/- 0.16 (vs.8.50 +/- 0.07 in rings), and BQ-123 (1 microM) caused a rightward shift of the ET-l induced concentration response curve (pKB 6.62 vs. 5.75 in rings).6. Contractile responses to big-ET-1 of endothelium-intact coronary artery segments were attenuated in the presence of phosphoramidon (100 microM), indicating conversion of big-ET-1 to ET-1 within the coronary artery segment.7. The present study indicates that ET-1 and sarafotoxin S6b contract the human isolated coronary artery via different receptors, which can probably be best characterized as subtypes of the ETA receptor.Furthermore, it is demonstrated that the type of preparation (ring or strip) may affect the potency of ET-1 as an agonist and of BQ-123 as an antagonist.
Bax
W A
WA
Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.
Aghai
Z
Z
van Tricht
C L
CL
Wassenaar
C
C
Saxena
P R
PR
D000293:Adolescent; D000328:Adult; D001381:Azepines / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003331:Coronary Vessels / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007223:Infant; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000819:agonists / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014757:Viper Venoms / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D007211:Indoles; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D011498:Protein Precursors; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C079574:FR 139317; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon