Exaggerated vascular and renal pathology in endothelin-b receptor-deficient rats with deoxycorticosterone acetate-salt hypertension

• Published in: Circulation (New York, N.Y.) Vol. 102; no. 22; pp. 2765 - 2773
• Main Authors: MATSUMURA, Yasuo, KURO, Toshihiko, KOBAYASHI, Yutaka, KONISHI, Fumiko, TAKAOKA, Masanori, WESSALE, Jerry L, OPGENORTH, Terry J, GARIEPY, Cheryl E, YANAGISAWA, Masashi
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 28-11-2000
• Subjects: Acetylglucosaminidase - urine; Animals; Animals, Genetically Modified; Aorta - drug effects; Aorta - pathology; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Blood Urea Nitrogen; Body Weight - drug effects; Cardiology. Vascular system; Desoxycorticosterone - pharmacology; Endothelin-1 - blood; Endothelin-1 - drug effects; Endothelin-1 - urine; Experimental diseases; Heart - drug effects; Heart - physiopathology; Hypertension - chemically induced; Hypertension - pathology; Hypertension - physiopathology; Kidney - drug effects; Kidney - pathology; Kidney - physiopathology; Medical sciences; Organ Size - drug effects; Rats; Rats, Mutant Strains; Receptor, Endothelin B; Receptors, Endothelin - deficiency; Receptors, Endothelin - genetics; Systole; Time Factors; Hypertension; Pathophysiology; Rat; Pathogenesis; Deficiency; Treatment efficiency; Rodentia; Cardiovascular disease; Endothelin 1; Genetic determinism; Kidney; Genetic disease; Salt; Vertebrata; Chemotherapy; Mammalia; Treatment; Gene; Animal; Antagonist; Mutation; Biological receptor
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.102.22.2765

Endothelin (ET)-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension. We evaluated the pathological role of ET(B) receptors in DOCA-salt-induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene.
Homozygous (sl/sl) rats exhibit abnormal development of neural crest-derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine ss-hydroxylase (DssH) promoter was used to direct ET(B) transgene expression in sl/sl rats to support normal enteric nervous system development. DssH-ET(B) sl/sl rats live into adulthood and are healthy, expressing ET(B) receptors in adrenal glands and other adrenergic neurons. When homozygous (sl/sl) and wild-type (+/+) rats, all of which were transgenic, were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than did wild-type rats. Chronic treatment with ABT-627, an ET(A) receptor antagonist, completely suppressed DOCA-salt-induced hypertension in both groups. Renal dysfunction and histological damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous rats than in wild-type rats. Renal and vascular injuries were significantly improved by ABT-627. In DOCA-salt-treated homozygous rats, there were notable increases in renal, urinary, and aortic ET-1, all of which were normalized by ABT-627.
ET(B)-mediated actions are protective in the pathogenesis of DOCA-salt-induced hypertension. Enhanced ET-1 production and ET(A)-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ET(B) receptor-deficient rats.