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


RESULTS
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.


CONCLUSIONS
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.
Matsumura
Y
Y
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan.
Kuro
T
T
Kobayashi
Y
Y
Konishi
F
F
Takaoka
M
M
Wessale
J L
JL
Opgenorth
T J
TJ
Gariepy
C E
CE
Yanagisawa
M
M
D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects*; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003900:Desoxycorticosterone / Q000494:pharmacology*; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects / Q000652:urine; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011922:Rats, Mutant Strains; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000172:deficiency* / Q000235:genetics; D013599:Systole; D013997:Time Factors
D019332:Endothelin-1; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D003900:Desoxycorticosterone; D000118:Acetylglucosaminidase