Journal
HYPERTENSION
Volume 46, Issue 1, Pages 87-92Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000170460.24604.23
Keywords
endothelin; arterial pressure; rabbits; plasma
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The precursor of endothelin-1, big endothelin-1, can be hydrolyzed by chymase to generate endothelin-1 ( 1-31) in vitro. In the present study, we explored the processes involved in the production of endothelin-1 ( 1-31) as well as its pharmacodynamic characteristics in the rabbit in vivo. Endothelin-1 ( 1-31) ( 1 nmol/kg, injected into the left cardiac ventricle) induced a monophasic increase of mean arterial blood pressure similarly to big endothelin-1 ( 1-38), whereas endothelin-1 induces a biphasic response. Phosphoramidon, a dual neutral endopeptidase and endothelin-converting enzyme inhibitor, blocked both pressor responses to endothelin-1 ( 1-31) and big endothelin-1 but not those afforded by endothelin-1. Thiorphan, a neutral endopeptidase inhibitor, markedly inhibited the response to endothelin-1 ( 1-31) but only weakly reduced that of big endothelin-1. In contrast, CGS 35066, an endothelin-converting enzyme inhibitor, was significantly more efficient against the pressor response to big endothelin-1 than to endothelin-1 ( 1-31). Furthermore, injection of big endothelin-1 concomitantly with phosphoramidon induced an increase in endothelin-1 ( 1-31) plasma levels. Finally, intracardiac-administered endothelin-1 ( 1-31) induced an increase of endothelin-1 plasma levels, which are markedly reduced by phosphoramidon and thiorphan but not by CGS 35066. Our results thus demonstrate that endothelin-1 ( 1-31) is an alternate intermediate in the production of endothelin-1 after big endothelin-1 administration in the rabbit in vivo.
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