title: Selective blockade of endothelin-B receptor improves survival of critically perfused musculocutaneous flaps.
abstract: OBJECTIVE
  Insufficient perfusion of distal flap areas, which may lead to partial necrosis, still represents a challenge in reconstructive surgery. In the process of microvascular and endothelial dysfunction, endothelins (ETs) and their receptors may play an important role. Therefore, the aim of the study was to investigate in a chronic in vivo model the effect of various ET-receptor antagonists in critically perfused flap tissue.
  
  
  METHODS
  A random pattern musculocutaneous flap was elevated in the back of 25 C57BL/6 mice and fixed into a dorsal skinfold chamber. Repetitive intravital fluorescence microscopy was performed over a 10-day observation period, assessing arteriolar diameter, arteriolar blood flow (aBF), functional capillary density (FCD), the area of tissue necrosis, and the development of newly formed blood vessels. ET-receptor blockers were administrated intraperitoneally 30 min before induction of ischemia, as well as daily during the subsequent 4-day period, including (1) BQ-123, a specific ET-A-receptor antagonist (ET-A = 1 mg/kg), (2) BQ-788, a selective ET-B-receptor antagonist (ET-B = 1 mg/kg), and (3) PD-142893, a nonselective ET-AB-receptor antagonist (ET-AB = 0.5 mg/kg). Animals receiving saline only served as controls (n = 7).
  
  
  RESULTS
  Despite an increase in aBF during the 10-day observation period (day 1 = 1.92 +/- 0.29 nl/s; day 10 = 4.70 +/- 1.64 nl/s), the flaps of saline-treated controls showed a distinct decrease in FCD (94 +/- 12 cm/cm(2)). This perfusion failure resulted in flap necrosis of 52 +/- 3%. Selective blockade of the ET-B receptor caused a further increase in aBF already at day 1 (2.97 +/- 0.42 nl/s), which persisted during the following 10-day observation period (day 10 = 5.74 +/- 0.69 nl/s). Accordingly, adequate FCD could be maintained (day 10 = 215 +/- 8 cm/cm(2); p < 0.05 vs control), resulting in a significant reduction in flap necrosis (day 10 = 25 +/- 4%; p < 0,05). In contrast, neither selective blockade of the ET-A receptor nor nonselective ET-A- and ET-B-receptor blockade were able to significantly affect aBF when compared to controls (day 1 = ET-A = 1.39 +/- 0.10 nl/s; ET-AB = 1.53 +/- 0.80 nl/s; n.s.). Accordingly, flap necrosis after ET-A- and ET-AB-receptor inhibition did not differ from that of controls (day 10 = ET-A: 46 +/- 10%; ET-AB = 51 +/- 7%).
  
  
  CONCLUSIONS
  Our data show that only selective ET-B-receptor inhibition is capable of maintaining nutritive perfusion and, hence, reducing necrosis in critically perfused flap tissue. Accordingly, administration of ET-B-receptor antagonists may be considered in the treatment of critically perfused flaps.
authors: Division of Plastic and Reconstructive Surgery, University Hospitals of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva, Switzerland.
authors: Reto
authors: R
authors: Wettstein
authors: Philipp
authors: P
authors: Mörsdorf
authors: Annick
authors: A
authors: Bächle
authors: Michaela
authors: M
authors: Amon
authors: Brigitte
authors: B
authors: Pittet
authors: Michael D
authors: MD
authors: Menger
authors: Yves
authors: Y
authors: Harder
mesh_terms: D000818:Animals; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D006085:Graft Survival; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012039:Regional Blood Flow; D013524:Surgical Flaps / Q000098:blood supply* / Q000473:pathology; D013997:Time Factors; D014699:Venules / Q000473:pathology / Q000503:physiopathology
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C076213:PD 142893; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)