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Different pharmacological profiles of big‐endothelin‐3 and big‐endothelin‐1 in vivo and in vitro
Author(s) -
D'OrléansJuste Pedro,
Télémaque Sabine,
Claing Audrey
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12448.x
Subject(s) - phosphoramidon , guinea pig , prostacyclin , thromboxane , endothelin receptor , endothelin 1 , endocrinology , medicine , endothelins , endothelin 3 , thromboxane b2 , chemistry , eicosanoid , platelet , arachidonic acid , enzyme , biochemistry , receptor
1 Human big‐endothelin‐1 (big‐ET‐1) and endothelin‐1 (ET‐1) are equipotent as pressor agents and produce a significant change in mean arterial blood pressure (MAP) in anaesthetized guinea‐pigs (2 nmol kg −1 : peak Δ MAP: 23 ± 6 mmHg and 26 ± 5 mmHg, respectively). 2 Unlike big‐ET‐1, big‐endothelin‐3 (big‐ET‐3) (10 and 20 nmol kg −1 ) induces no pressor responses whereas endothelin‐3 (ET‐3) at 2 nmol kg −1 induces a significant increase of blood pressure in anaesthetized guinea‐pigs (peak Δ MAP: 27 ± 5 mmHg) with a shorter duration than ET‐1 and big‐ET‐1. 3 Big‐ET‐1 at concentrations 40 times higher than those required for ET‐1 (2.5 n m ) releases prostacyclin (PGI 2 ) (maximal release: 2.7 ± 0.8 ng ml −1 ; 2.9 ± 0.9 ng ml −1 , respectively) and thromboxane B 2 (TxB 2 ) (maximal release: 6.7 ± 1.3 ng ml −1 ; 6.8 ± 1.1 ng ml −1 , respectively) from guinea‐pig perfused lungs. ET‐3 (2.5 n m ) is also a potent releaser of PGI 2 and TxB 2 from the guinea‐pig lungs (maximal release: PGI 2 : 2.4 ± 1.0 ng ml −1 ; TxB 2 : 3.8 ± 0.6 ng ml −1 ). Conversely, big‐ET‐3 (100 n m ) does not increase basal release of eicosanoids. 4 Phosphoramidon (50 μ m ), a metalloprotease inhibitor, markedly reduced the eicosanoid releasing properties of big‐ET‐1 ( n = 4, P < 0.01) in guinea‐pig perfused lungs without affecting the release stimulated by ET‐1. 5 Our results suggest that big‐ET‐1 is converted to ET‐1 via a phosphoramidon‐sensitive endothelin converting enzyme (ECE) to release eicosanoids. The ECE is present in the guinea‐pig pulmonary vasculature. Furthermore, our results suggest that the ECE activity is specific for big‐ET‐1 and may not convert big‐ET‐3 to its active metabolite, ET‐3.