Evidence for vasoconstriction mediated by the endothelin-B receptor in domestic swine.
Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in a number of cardiovascular diseases, including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertension. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET(A) receptors on vascular smooth muscle cells. Recent studies have indicated that vasoconstriction also may be mediated by stimulation of an ET(B)-receptor subtype. Increased use of the pig as a cardiovascular model prompted us to examine the receptor profile in this species using ABT-627, a potent, nonpeptide antagonist of the ET(A) receptor. The precursor to ET-1, big ET-1 (0.02 nmol/kg/min), was infused intravenously in domestic swine, resulting in a sustained increase in mean blood pressure of 38 +/- 3 mm Hg. After stabilization of the pressor response, ABT-627 (0.1-10 microg/kg/min) or vehicle was infused for 30 min. Whereas vehicle infusion had no appreciable effect, a dose-related reversal of the pressor response to big ET-1 (11-100%) was observed by the end of the ABT-627 infusion. Blood samples were assayed for plasma concentrations of ABT-627; peak levels ranged from 9 +/- 2 to 937 +/- 168 ng/ml. In a separate group of pigs, the highest dose of ABT-627 produced only a modest reversal of the hypertensive response to an infusion of angiotensin II (300 ng/kg/min). Additional results indicate that the vasoconstrictor effects produced by sarafotoxin 6C (0.03 and 0.3 nmol/kg), an agonist of the ET(B) receptor, are not blocked by treatment with ABT-627 (10 microg/kg/min). However, complete blockade of the S6C response could be achieved using the ET(B) antagonist, A-192621 (0.33 mg/kg/min). Our results define the dose-response relation for the ET(A)-receptor antagonist ABT-627 in the vasculature of the domestic pig and suggest the presence of an ET(B)-receptor subtype that mediates vasoconstriction in this species.
Burke
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SE
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. sandra.e.burke@Abbott.com
Nelson
R A
RA
Lubbers
N L
NL
Ford
T T
TT
Fu
K I
KI
Padley
R J
RJ
Wegner
C D
CD
Cox
B F
BF
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000829:Animals, Domestic; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000097:blood / Q000494:pharmacology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000097:blood / Q000494:pharmacology; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D000804:Angiotensin II; D000077868:Atrasentan