Effects of separate and combined eta and etb blockade on
endothelin-1-induced constriction in perfused rat lungs.
Sato, Koichi, Masahiko Oka, Kiichi Hasunuma, Masahiro Ohnishi,
Kazuhiko Sato, and Shiro Kira.
Department of Respiratory Medicine, Juntendo University School of
Medicine, Tokyo, 113, Japan
APStracts 2:0124L, 1995.
To evaluate the role of endothelin (ET) receptors in ET-1-induced
pulmonary vasoreactivity, we studied the effects of ET receptor
agonists and antagonists in isolated perfused rat lungs. ET-1 (1-10
nM) caused concentration-dependent pulmonary vasoconstriction and
gross pulmonary edema at a concentration of 10 nM. The combination of
the selective ETA antagonist BQ123 and the selective ETB antagonist
BQ788 inhibited ET-1-induced pulmonary vasoconstriction more
effectively than BQ123 alone, whereas BQ788 alone enhanced the
constriction. ET-1-induced hydrostatic pulmonary edema was prevented
by the combination of BQ123 and BQ788, but not by either BQ123 or
BQ788 alone. After the addition of 125 ng of exogenous ET-1, the
perfusate levels of ET-1 were significantly higher in BQ788-treated
lungs than either the vehicle control or BQ123-treated lungs. The
selective ETB agonist IRL1620 also caused pulmonary vasoconstriction
and edema, both of which were completely inhibited by BQ788. ET-1
-induced transient vasodilation was abolished by BQ788 but unaffected
by BQ123. These results suggest that in the isolated perfused rat
lung, ET-1-induced vasoconstriction is mediated by both ETA and ETB
receptors, whereas ET-1-induced transient vasodilation is mediated
exclusively by the ETB receptor. Blockade of ETB receptors may result
in enhanced ET-1 activity (via the ETA receptor) through inhibition
of the ETB-mediated clearance of ET-1. Thus, combined ETA and ETB
blockade is required for the complete inhibition of ET-1-induced
vasoconstriction in the rat pulmonary circulation.
Received 21 March 1995; accepted in final form 12 July 1995.
APS Manuscript Number L89-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 July 1995.