ETA receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor ABT-869 in telemetry-instrumented rats.
ABT-869 is a novel multitargeted inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases (RTKs) with potent antiangiogenic properties that slow tumor progression. Vascular endothelial growth factor receptor blockade has been shown to produce hypertension. Atrasentan is a potent and selective endothelin (ETA) receptor antagonist that lowers blood pressure and affects tumor growth. To assess the utility of ETA receptor blockade in controlling hypertension with RTK inhibition, we evaluated the ability of atrasentan to block hypertension with ABT-869 in conscious, telemetry-instrumented rats. Changes in mean arterial pressure (MAP) and heart rate (HR) were evaluated using mean values and the area under the curve (AUC). Atrasentan (0.5, 1.5, and 5.0 mg kg(-1) d(-1) for 5 days) elicited dose-dependent decreases in MAP-AUC (-16.7 +/- 1.3, -20.94 +/- 3.68, and -30.12 +/- 3.57 mm Hg x day, respectively) compared with vehicle. ABT-869 (1, 3, 10, 30 mg kg(-1) d(-1) for 5 days) increased MAP compared with vehicle (MAP-AUC values of -5.52 +/- 3.75, 12.7 +/- 8.4, 37.5 +/- 4.4, and 63.8 +/- 3.3 mm Hg x day, respectively). Pretreatment with atrasentan (5 mg/kg for 5 days) prevented and abolished the hypertensive effects of ABT-869. Thus, ETA receptor blockade effectively alleviated hypertension with RTK inhibition and may serve a dual therapeutic role by preventing hypertension and slowing tumor progression.
Banfor
Patricia N
PN
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA. patricia.banfor@abbott.com
Franklin
Pamela A
PA
Segreti
Jason A
JA
Widomski
Deborah L
DL
Davidsen
Steven K
SK
Albert
Daniel H
DH
Cox
Bryan F
BF
Fryer
Ryan M
RM
Gintant
Gary A
GA
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007191:Indazoles / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013686:Telemetry
D020533:Angiogenesis Inhibitors; D065130:Endothelin A Receptor Antagonists; D007191:Indazoles; D010671:Phenylurea Compounds; D011759:Pyrrolidines; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D000077868:Atrasentan