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Differential pharmacological profile of endothelin-1 and its precursor, big endothelin.
Differential pharmacological profile of endothelin-1 and its precursor, big endothelin.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 1991; Vol. 17 Suppl 7, pp. S362-5. - Publication Year :
- 1991
-
Abstract
- In pentobarbital-anesthetized rats endothelin-1 (ET-1), endothelin-2 (ET-2), endothelin-3 (ET-3), and mouse ET-2 (mET-2), in contrast to human big ET-1 (h-big ET), administered as i.v. bolus injections (0.25 nmol/kg i.v.) produced rapidly appearing and short-lasting blood pressure decreases. This effect was markedly inhibited (80-100%) after an 8-min i.v. infusion (0.1 nmol/kg/min over 10 min) of any of the ET studied, but not by h-big ET, the precursor of ET-1. Similarly, in pithed rats given a 10 min i.v. infusion of an equipressor dose (0.1 nmol/kg/min) of ET-1 or h-big ET, the hypotensive effects of ET-1 were entirely blocked only in the group of animals pretreated with ET-1. In pithed rats, ET-1 (0.25 nmol/kg i.v.) and h-big ET (0.5 nmol/kg i.v.) produced equivalent maximal pressor responses and the same pattern of increase in systemic, hindquarter, and renal vascular resistance. However, ET-1 was three times more potent than h-big ET as a vasoconstrictor of the mesenteric bed. Also the pressor response to h-big ET, but not ET-1 (0.25 nmol/kg i.v.), was markedly inhibited by the metalloprotease inhibitor phosphoramidon (5 mg/kg i.v.). These results indicate that the hypotensive effects of ET isopeptides have a common mechanism because they elicit cross tachyphylaxis, although h-big ET did not inhibit the decrease in blood pressure produced by ET-1. A possible explanation for this finding is that h-big ET has intrinsic pressor activity but does not have affinity for receptors mediating the vasodepressor effects of ET isoforms. Alternatively, h-big ET is converted into ET-1 too slowly to yield biophase concentrations of ET-1 necessary for lowering blood pressure and developing tachyphylaxis to ET-isoform-induced hypotension. Finally, if the pressor effects of h-big ET are mediated by ET-1 formation, phosphoramidon can be considered as an inhibitor of the endothelin-converting enzyme.
- Subjects :
- Animals
Decerebrate State
Endothelin-1
Endothelins antagonists & inhibitors
Glycopeptides pharmacology
Male
Protein Precursors antagonists & inhibitors
Rats
Regional Blood Flow drug effects
Tachyphylaxis physiology
Blood Pressure drug effects
Endothelins pharmacology
Protein Precursors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0160-2446
- Volume :
- 17 Suppl 7
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 1725381
- Full Text :
- https://doi.org/10.1097/00005344-199100177-00103