Nephroprotective effects of the endothelin ET(A) receptor antagonist darusentan in salt-sensitive genetic hypertension.
We tested the effect of selective endothelin ET(A) receptor blockade on the development renal damage in the Sabra rat model of genetic salt-sensitivity. Animals from the salt-sensitive (SBH/y) and salt-resistant strains (SBN/y) were either salt-loaded with deoxycorticosterone acetate and salt (DOCA) or fed a normal diet. Additional salt-loaded groups were also treated with the selective ET(A) antagonist darusentan (DA). Salt-loading in SBH/y increased systolic blood pressure by 75 mm Hg and urinary albumin excretion 23-fold (P<0.0001). Darusentan attenuated the rise of systolic blood pressure (50%) and urinary albumin excretion (63%, P<0.01, respectively). Salt-loading in SBH/y was associated with significant increased osteopontin mRNA expression as well as glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.05, respectively). This was either significantly reduced or normalized by darusentan (P<0.05, respectively). Thus, darusentan confers a significant renal protection in the Sabra model of salt-sensitive hypertension.
Rothermund
Lars
L
Institut für Klinische Pharmakologie und Toxikologie, Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.
Traupe
Tobias
T
Dieterich
Maike
M
Kossmehl
Peter
P
Yagil
Chana
C
Yagil
Yoram
Y
Kreutz
Reinhold
R
D000419:Albuminuria / Q000150:complications; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000652:urine; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D007668:Kidney; D007674:Kidney Diseases / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D053495:Osteopontin; D010666:Phenylpropionates / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics; D044022:Receptor, Endothelin A / Q000187:drug effects* / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000378:metabolism; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000009:adverse effects*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012795:Sialoglycoproteins; D017673:Sodium Chloride, Dietary; C506897:Spp1 protein, rat; D053495:Osteopontin; C107831:darusentan; D003900:Desoxycorticosterone; D012964:Sodium