Chronic activation of endothelin B receptors: new model of experimental hypertension.
Endothelin (ET) exerts powerful pressor actions primarily through activation of the ET(A) receptor subtype. The ET(B) receptor (ET(B)R) subtype, on the other hand, is generally thought to initiate physiological actions that decrease arterial pressure. Such actions include clearing ET from the bloodstream, initiating endothelium-mediated vasodilation, and facilitating renal sodium and water excretion. The effect of long-term activation of the ET(B)R on arterial pressure, however, never has been directly tested. In this study we evaluated cardiovascular responses to chronic (5-day) activation of ET(B)R in male rats using continuous intravenous infusion of the selective agonist sarafotoxin 6c. Surprisingly, we found that sarafotoxin 6c caused a sustained increase in arterial pressure that rapidly reversed on termination of infusion. The hypertension was associated with increased renal excretion of sodium and water and decreased plasma volume. Alterations in daily sodium intake did not affect the magnitude of the hypertension. Hemodynamic studies revealed a decreased cardiac output and increased total peripheral resistance during sarafotoxin 6c infusion. Infusion of sarafotoxin 6c caused a small increase in plasma ET levels. Nevertheless, the hypertension was not affected by coadministration of a selective ET(A) receptor antagonist (atrasentan) but was completely prevented by treatment with a combined ET(A) receptor and ET(B)R antagonist (A186280). These experiments reveal for the first time that chronic activation of ET(B)R in rats causes sustained hypertension.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA. finkg@msu.edu
Gregory
G
Fink
Melissa
M
Li
Yanny
Y
Lau
John
J
Osborn
Stephanie
S
Watts
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D001810:Blood Volume / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D004334:Drug Administration Schedule; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006339:Heart Rate; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000819:agonists* / Q000378:metabolism; D013318:Stroke Volume; D013449:Sulfonamides / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014757:Viper Venoms / Q000008:administration & dosage* / Q000494:pharmacology
C467893:A 182086; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D014757:Viper Venoms; C057354:sarafotoxins s6; D000077868:Atrasentan