ET(B) receptor blockade potentiates the pressor response to big endothelin-1 but not big endothelin-2 in the anesthetized rabbit.
The precursor of endothelin-1, big endothelin-1, is considered to be a more reliable marker of systemic production of vasoactive peptide. However, it is largely unclear whether ET(B) receptor-dependent clearance and endothelium-derived relaxing factors affect the precursor in a similar manner to mature ET-1. These ET(B)-dependent modulations of big ET-1 and big ET-2 pressor properties were therefore studied in the anesthetized rabbit. When injected into the left cardiac ventricle, ET-1 and ET-2 (0.01 to 1 nmol/kg) each induced biphasic responses (a depressor followed by a pressor response), whereas big ET-1 and big ET-2 (0.1 to 3 nmol/kg) caused only protracted pressor responses. The highest dose of big ET-1 caused significantly greater responses than ET-1, ET-2, or big ET-2. A selective ET(A) receptor antagonist, BQ-123 (1 mg/kg), markedly reduced pressor responses to all 4 peptides, whereas blockade of ET(B) receptors with BQ-788 (0.25 mg/kg) sharply potentiated the responses to ET-1, ET-2, and big ET-1, but not to big ET-2. Indomethacin (10 mg/kg) sharply potentiated the pressor response to ET-1 (1 nmol/kg), but not big ET-1, at all time points. In control animals, ET-1, but not big ET-1, also triggered an indomethacin-sensitive increase in circulating prostacyclin. Finally, systemically administered big ET-1, but not big ET-2, induced a phosphoramidon-sensitive increase in plasma IR-ET. Our results suggest a significant limiting role of ET(B) receptors on pressor responses to big ET-1. In contrast, the same receptor entities do not modulate the hemodynamic properties of the ET-2 precursor, given that, unlike big ET-1, it is poorly converted in the pulmonary or systemic circulation in anesthetized rabbits.
Gratton
J P
JP
Department of Pharmacology, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA.
Rae
G A
GA
Bkaily
G
G
D'Orléans-Juste
P
P
D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001794:Blood Pressure; D002851:Chromatography, High Pressure Liquid; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000097:blood / Q000494:pharmacology; D019333:Endothelin-2 / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D019334:Endothelin-3 / Q000032:analysis / Q000097:blood; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D011464:Epoprostenol / Q000097:blood; D005260:Female; D008297:Male; D008666:Metalloendopeptidases; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D016232:Endothelins; D009842:Oligopeptides; D010880:Piperidines; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D009569:Nitric Oxide; C086539:BQ 788; D011464:Epoprostenol; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes