In vivo characterization of a phosphoramidon-sensitive endothelin-converting enzyme in the rat
| Autor: | Eugene I. Novosad, Barbara J. Divish, Neal S. Burres, Ivan Milicic, Terry J. Opgenorth, David M. Pollock |
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| Rok vydání: | 1993 |
| Předmět: |
Male
medicine.medical_specialty Blood Pressure Pressoreceptors Muscle Smooth Vascular Rats Sprague-Dawley chemistry.chemical_compound In vivo Internal medicine medicine Animals Humans Potency Drug Interactions Receptor EC50 Pharmacology Receptors Endothelin Chemistry Endothelins Phosphoramidon Glycopeptides respiratory system Rats Endocrinology Vasoconstriction Injections Intravenous Big Endothelin 3 Neprilysin medicine.symptom Endothelin receptor |
| Zdroj: | European Journal of Pharmacology. 231:459-464 |
| ISSN: | 0014-2999 |
| Popis: | Experiments were conducted to characterize the nature of a phosphoramidon-sensitive endothelin-converting enzyme in vivo by evaluating the pressor response to a bolus intravenous (i.v.) injection of endothelin family peptides following administration of phosphoramidon in anesthetized Sprague-Dawley rats. Phosphoramidon given i.v. at 10 mg/kg completely prevented the pressor response to human big endothelin-1-(1-38) (big ET-1). The EC50 for phosphoramidon was determined to be in the range of 1 to 3 mg/kg. The pressor response to big ET-1 60 min after phosphoramidon injection was attenuated by roughly 60% indicating a long inhibitory half-life. Very high doses of big ET-1 (> 20 mg/kg) were capable of over-riding the effect of phosphoramidon and produced characteristic pressor responses suggesting that the inhibition by phosphoramidon can be considered competitive in nature. Human big endothelin-3-(1-41) (big ET-3) produced significant increases in arterial pressure although with less potency and efficacy compared to big ET-1. The pressor response to big ET-3 was also inhibited by phosphoramidon. Phosphoramidon does not act indirectly by interfering with ET-1 receptor-mediated actions since the inhibitor has no effect on the in vivo pressor response to ET-1 and does not antagonize [125I]ET-1 receptor binding or constrictor responses in vitro. These results are consistent with the idea that a phosphoramidon-sensitive endothelin-converting enzyme is capable of cleaving both big ET-1 and big ET-3 to the active peptides in the rat. |
| Databáze: | OpenAIRE |
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