Contrasting effects of intervention with ETA and ETB receptor antagonists in hypertension induced by angiotensin II and high-salt diet.
Endothelin (ET) receptor antagonists are antihypertensive and renoprotective in angiotensin II (AngII)-induced hypertension if administered when AngII infusion commences, but their effects on established hypertension are poorly understood. We therefore tested the effects of intervening with an ETA (ABT-627) or ETB (A-192621) receptor antagonist after establishing hypertension with AngII (65 ng/min s.c.) plus 8% NaCl diet (AngII-HS) in rats. Prior to administration of ABT-627, AngII-HS and AngII-HS plus ABT-627 groups displayed robust hypertension (mean arterial pressure (MAP), 170 +/- 5 and 165 +/- 5 mm Hg versus 110 +/- 3 mm Hg in normal salt control rats at day 7, P < 0.05). Administering ABT-627 from day 8 of AngII-HS treatment prevented further rises in MAP (168 +/- 5 and 191 +/- 3 mm Hg at day 13 in AngII-HS plus ABT-627 and AngII-HS, P < 0.001), without blunting the significant increases in urinary protein (19-fold), albumin (25-fold), or MCP-1 excretion (6- to 8-fold) or the reduction in creatinine clearance. Administering A-192621 from day 8 mildly exacerbated AngII-HS induced hypertension (P < 0.05 for AngII-HS versus AngII-HS plus A-192621 on days 11 and 12 only) and reduced plasma nitrite/nitrate concentration (P < 0.05), without affecting proteinuria, albuminuria, or creatinine clearance. These results confirm the importance of ETA receptor signaling in maintaining AngII-HS hypertension and suggest that including ETB receptor blockade in therapeutic approaches to treating hypertension would be ineffective or even counterproductive.
Boesen
Erika I
EI
Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912, USA. eboesen@mcg.edu
Pollock
Jennifer S
JS
Pollock
David M
DM
D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology / Q000652:urine; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009566:Nitrates / Q000097:blood / Q000652:urine; D009573:Nitrites / Q000097:blood / Q000652:urine; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D016896:Treatment Outcome
C120508:A 192621; D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D009566:Nitrates; D009573:Nitrites; D011759:Pyrrolidines; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D000077868:Atrasentan