PMID- 10961375
OWN - NLM
STAT- MEDLINE
DCOM- 20010202
LR  - 20211214
IS  - 0028-1298 (Print)
IS  - 0028-1298 (Linking)
VI  - 362
IP  - 2
DP  - 2000 Aug
TI  - Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on 
      endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin 
      release.
PG  - 128-36
AB  - Endothelins are a family of potent endogenous mediators that have been implicated 
      in a number of airway and other diseases. Recently, the non-peptide mixed 
      ET(A)/ET(B) endothelin receptor antagonist bosentan has been successfully tested 
      in the treatment of cardiovascular diseases. It was the aim of the present study 
      to characterize the effects of bosentan on the pulmonary actions of endothelin- 
      (ET-1), endothelin-3 (ET-3) and the ET(B)-receptor agonist IRL1620 in the 
      isolated perfused and ventilated rat lung (IPL) and in precision-cut lung slices 
      (PCLS). In the IPL, bosentan completely prevented the IRL1620-induced 
      vasoconstriction (IC50 3 microM). The inhibition by bosentan of ET-1-elicited 
      vasoconstriction showed a biphasic course, reflecting the inhibition of ET(A)-and 
      ET(B)-mediated vasoconstriction (IC50 0.2 microM and 19 microM, respectively). In 
      addition, bosentan prevented the ET-1- (IC50 6 microM) and IRL1620-induced (IC50 
      3 microM) prostacyclin release. Bosentan also completely prevented the 
      bronchoconstriction induced by IRL1620 in the IPL (IC50 20 microM) and in PCLS 
      (IC50 13 microM). In PCLS, the pD2-values were ET-1 7.20+/-0.23, ET-3 7.51+/-0.27 
      and IRL1620 7.33+/-0.29. Bosentan at 100 microM caused a rightward shift of the 
      concentration-response curve of ET-1, ET-3 and IRL1620 by a factor of 5, 46 and 
      64, respectively. In all cases the slope of the Schild regression was lower than 
      unity, disregarding a simple interaction of bosentan with one receptor. With 
      respect to ET-1-induced bronchoconstriction, in the IPL bosentan in 
      concentrations of up to 10 microM aggravated ET-1-induced bronchoconstriction 
      probably due to the blockade of bronchodilatory ET(A)-receptors (IC50 0.3 microM) 
      and even at 100 microM showed only very little protection from ET- -induced 
      bronchoconstriction in the IPL and in the PCLS. The similar IC50-values for 
      ET-1-induced vasoconstriction and bronchodilation suggest that only one type of 
      ET(A)-receptor is involved. The differing IC50-values between IRL1620-induced 
      bronchoconstriction and prostacyclin release, the slope of the Schild regression 
      and the failure of bosentan to prevent the ET-1-induced bronchoconstriction 
      suggest a complex interaction between the known ET-receptors or the existence of 
      unknown ET(B)-receptor subtypes.
FAU - Martin, C
AU  - Martin C
AD  - Division of Pulmonary Pharmacology, Research Centre Borstel, Germany.
FAU - Held, H D
AU  - Held HD
FAU - Uhlig, S
AU  - Uhlig S
LA  - eng
PT  - Journal Article
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Endothelin Receptor Antagonists)
RN  - 0 (Endothelin-1)
RN  - 0 (Endothelin-3)
RN  - 0 (Endothelins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptor, Endothelin A)
RN  - 0 (Receptor, Endothelin B)
RN  - 0 (Sulfonamides)
RN  - 11X778QIZS (sovateltide)
RN  - DCR9Z582X0 (Epoprostenol)
RN  - Q326023R30 (Bosentan)
SB  - IM
MH  - Animals
MH  - Antihypertensive Agents/*pharmacology
MH  - Area Under Curve
MH  - Bosentan
MH  - Bronchoconstriction/*drug effects
MH  - *Endothelin Receptor Antagonists
MH  - Endothelin-1/metabolism
MH  - Endothelin-3/pharmacology
MH  - Endothelins/*antagonists & inhibitors/pharmacology
MH  - Epoprostenol/*metabolism
MH  - Female
MH  - Image Processing, Computer-Assisted
MH  - In Vitro Techniques
MH  - Lung/metabolism
MH  - Peptide Fragments/pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, Endothelin A
MH  - Receptor, Endothelin B
MH  - Respiratory Mechanics/drug effects
MH  - Sulfonamides/*pharmacology
MH  - Vasoconstriction/*drug effects
EDAT- 2000/08/29 11:00
MHDA- 2001/03/03 10:01
CRDT- 2000/08/29 11:00
PHST- 2000/08/29 11:00 [pubmed]
PHST- 2001/03/03 10:01 [medline]
PHST- 2000/08/29 11:00 [entrez]
AID - 10.1007/s002100000264 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):128-36. doi: 
      10.1007/s002100000264.