title: Endothelin-1 and -2: two amino acids matter.
abstract: OBJECTIVE
  Endothelin-1 (ET-1) and endothelin-2 (ET-2; Trp(6)Leu(7)ET-1) are expressed by different cell types, but are considered to display identical pharmacological properties on endothelin receptors. We studied agonist-dependent aspects of endothelin(A) (ET(A))-receptor function and the importance of amino acids 6 and 7 of ET-1 and ET-2 in this respect.
  
  
  METHODS
  We used isolated rat mesenteric resistance arteries in wire myographs, in a setting that minimizes influences of endothelium and sensorimotor nerves, to study arterial smooth muscle ET(A)-receptor-mediated vasomotor responses, to ET-1, ET-2 and chimeras thereof (Trp(6)ET-1 and Leu(7)ET-1).
  
  
  RESULTS
  ET-1 and ET-2 cause arterial contractions with comparable sensitivities and maximal responses. BQ123 (ET(A)-antagonist) reduces sensitivity to ET-1 more potently than that to ET-2 (pK(B): 7.1 ± 0.2 versus 5.6 ± 0.4). However, 1 μM BQ123 relaxes maximal contractile responses to ET-2 more markedly than those to ET-1. Leu(7)ET-1 is a contractile agonist with lower potency and similar maximal effect compared to ET-1 and greater sensitivity to BQ123 than ET-2. Up to 256 nM Trp(6)ET-1 did not cause contraction and did not antagonize arterial responses to ET-1.
  
  
  CONCLUSIONS
  Arterial smooth muscle ET(A)-receptor function displays agonist-dependent aspects. This involves roles of amino acids on position 6 and 7 of the endothelin sequence. Agonist-dependent pathologies may benefit from the design of specific, agonist-selective ET-receptor antagonists.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Matthijs G
authors.initials: MG
authors.lastname: Compeer
authors.forename: Dennis P L
authors.initials: DP
authors.lastname: Suylen
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019332:Endothelin-1 / Q000737:chemistry / Q000378:metabolism*; D019333:Endothelin-2 / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A / Q000819:agonists / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D019333:Endothelin-2; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)