A specific endothelin-1 antagonist blocks inhaled endothelin-1-induced bronchoconstriction in sheep.
In this study we used conscious sheep to compare the relative potencies of inhaled endothelin- (ET) 1 and ET-3 and to determine whether a newly described selective ET-1 receptor antagonist, [diaminopropionic acid1-Asp15]ET-1 ([Dpr1-Asp15]ET-1), when given as an aerosol blocks ET-1-induced bronchoconstriction. Partial concentration-response curves to ET-1 and ET-3 were obtained by measuring the change in pulmonary airflow resistance (RL) after aerosol challenge. Both ET-1 (n = 6) and ET-3 (n = 4) caused concentration-dependent (10(-10)-10(-7) bronchoconstriction, but ET-3 was 400-fold less potent than ET-1. Pretreatment (30 min) with 25 breaths of 5 x 10(-8) M [Dpr1-Asp15]ET-1 caused a 100-fold rightward shift of the ET-1 concentration-response curve. The activity of the ET-1 antagonist (25 breaths of 5 x 10(-8) M) was compared with that of various control peptides (25 breaths of 10(-8) M). ET-1 (50 breaths of 10(-7) M) caused an increase in RL of 133 +/- 33% (SE) over baseline. [Dpr1-Asp15]ET-1 significantly inhibited this response by 54%. No protection was seen with a monocyclic control peptide or a thrombin receptor peptide. There was, however, a small protective effect (38%, P < 0.05) seen with [Dpr1-Asp15]ET-3, a structurally homologous ET-3 antagonist. [Dpr1-Asp15]ET-1 had no effect on carbachol (n = 3) or leukotriene D4-induced bronchoconstriction. Thus inhaled ET-1 and, to a lesser extent, ET-3 cause concentration-dependent bronchoconstriction in conscious sheep.(ABSTRACT TRUNCATED AT 250 WORDS)
Abraham
W M
WM
Division of Pulmonary Diseases, University of Miami, Mount Sinai Medical Center, Miami Beach, Florida 33140.
Ahmed
A
A
Cortes
A
A
Spinella
M J
MJ
Malik
A B
AB
Andersen
T T
TT
D000336:Aerosols; D000595:Amino Acid Sequence; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D016232:Endothelins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015656:Respiratory Mechanics / Q000187:drug effects; D013189:SRS-A / Q000494:pharmacology; D012756:Sheep
D000336:Aerosols; D016232:Endothelins; D013189:SRS-A; C082327:endothelin 1, Dpr(1)-Asp(15)-; D002217:Carbachol