title: Blunted vascular response to endothelin-a receptor blockade in cyclosporine-treated lung transplant recipients.
abstract: BACKGROUND
  The majority of cyclosporine-treated transplant recipients develop hypertension. Endothelin-1 (ET-1) has been suggested to mediate cyclosporine-induced vasoconstriction when binding to ET-A receptors. We hypothesized that cyclosporine-treated lung transplant recipients have an increased basal vascular resistance and an augmented response to ET-A receptor blockade.
  
  
  METHODS
  The selective ET-A receptor blocker BQ-123 (10 and 50 nmol/min) was infused into the brachial artery, alone or in combination with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (2 and 4 micromol/min) in 10 lung transplant recipients without pharmacologically treated hypertension and 8 healthy controls. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and plasma levels of ET-1 were analyzed.
  
  
  RESULTS
  Baseline forearm vascular resistance did not differ between recipients and controls (32 +/- 4 vs 42 +/- 7 mmHg/ml/min, p = 0.32). BQ-123 increased FBF in controls but not in recipients (26% +/- 9% vs 5% +/- 11% at 10 nmol/min, p = 0.043 between groups). Coinfusion of BQ-123 and L-NMMA caused a comparable decrease in FBF in recipients and controls (-26% +/- 11%, vs -34% +/- 7%). Baseline ET-1 was higher in recipients (17.2 +/- 1.1 vs 14.7 +/- 0.8 pg/ml, p = 0.038). BQ-123 infusion increased plasma ET-1 in controls but not in recipients (+24% +/- 11% vs -0.4% +/- 6.2%, p = 0.029 between groups).
  
  
  CONCLUSIONS
  The results demonstrate that cyclosporine-treated lung transplant recipients have increased plasma levels of ET-1 and a blunted response to ET-A receptor blockade compared with healthy subjects. In contrast, we found no evidence for an increased basal vascular resistance in transplant recipients. These alterations in endothelin handling may contribute to the development of transplant-associated hypertension.
authors.affiliation: Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Silverborn
authors.forename: Anneli
authors.initials: A
authors.lastname: Ambring
authors.forename: Folke
authors.initials: F
authors.lastname: Nilsson
authors.forename: Peter
authors.initials: P
authors.lastname: Friberg
authors.forename: Anders
authors.initials: A
authors.lastname: Jeppsson
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016572:Cyclosporine / Q000627:therapeutic use; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007261:Infusions, Intra-Arterial; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; D019323:omega-N-Methylarginine; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; C072247:cyclo(Trp-Asp-Pro-Val-Leu)