Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats

Pulm Pharmacol Ther. Apr-Jun 1998;11(2-3):221-5. doi: 10.1006/pupt.1998.0142.

Abstract

Previous evidence suggests a role for endothelin-1 (ET-1) in the pathogenesis of pulmonary fibrosis. To determine if ET-1 regulates collagen deposition in pulmonary fibrosis, we examined the effect of the non-selective ETA and ETB receptor antagonist bosentan (Ro 47-0203), and a selective ETA receptor antagonist, BQ-485, on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung collagen content, derived from measurements of hydroxyproline and expressed as mg collagen/lung, was increased in the bleomycin-treated animals by day 7 (bleomycin, 22.88+/-1.46; control 18.50+/-0.98; P<0.05), continued to increase up to day 14 (bleomycin, 38.80+/-2.17; control 22.57+/-0.77; P<0.001) and then remained constant to 21 days. Daily treatment by gavage with bosentan (100 mg/kg) did not prevent the increase in collagen deposition induced by instillation of bleomycin at any of the times measured. Continuous administration of BQ-485, by subcutaneously implanted minipump (7.5 mg/day), also failed to prevent the bleomycin-induced collagen deposition at 14 days. These findings suggest that ET-1 does not modulate collagen deposition during the development of bleomycin-induced pulmonary fibrosis. Further studies are required to assess whether endothelin receptor antagonists modulate other components of the fibrotic response or play a role in man.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / pharmacology
  • Antimetabolites, Antineoplastic / toxicity*
  • Azepines / administration & dosage
  • Azepines / pharmacology
  • Bleomycin / toxicity*
  • Bosentan
  • Collagen / metabolism*
  • Endothelin Receptor Antagonists*
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / physiopathology
  • Rats
  • Rats, Inbred Lew
  • Receptors, Endothelin / physiology
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology

Substances

  • Antihypertensive Agents
  • Antimetabolites, Antineoplastic
  • Azepines
  • Endothelin Receptor Antagonists
  • Oligopeptides
  • Receptors, Endothelin
  • Sulfonamides
  • Bleomycin
  • BQ 485
  • Collagen
  • Bosentan