title: Renoprotective effects of a combined endothelin type A/type B receptor antagonist in experimental malignant hypertension.
abstract: We previously showed that plasma endothelin-1 (ET-1) concentration was increased in deoxycorticosterone acetate (DOCA)-salt-induced malignant hypertension in spontaneously hypertensive rats (SHR). In contrast, in normal SHR, this value is similar to that seen in Wistar-Kyoto (WKY) rats. The purpose of this study was to examine the effects of the new combined ET type A/type B (ETA/B) receptor antagonist, TAK-044, on the development of hypertension in this model of malignant hypertension. TAK-044 10 mg/kg, which effectively blocks both ETA and ETB receptors, was administered intraperitoneally once per day for 4 weeks in DOCA-salt SHR, and the effects on ET-1 and other parameters were compared with the same values in untreated WKY rats, untreated DOCA-salt SHR, and hydralazine-treated DOCA-salt SHR. DOCA-salt caused marked increases in blood pressure, blood urea nitrogen (BUN), serum creatinine, and plasma ET-1 concentrations in SHR. Both TAK-044 and hydralazine significantly suppressed the increase in blood pressure in DOCA-salt SHR to the same extent. Both treatments also suppressed the increase in BUN and serum creatinine, but this attenuation was less marked with hydralazine than with TAK-044. Neither TAK-044 nor hydralazine affected plasma ET-1 concentration in this model. TAK-044 significantly reduced kidney weight in DOCA-salt SHR, whereas the decrease seen with hydralazine was less marked. Prevention of DOCA-salt-induced renal structural injury (mesangial hypercellularity, glomerular sclerotic changes, and tubulointerstitial damage) in this model was clearly greater with TAK-044 treatment than with hydralazine treatment. These results suggest that endogenous ET-1 may, at least in part, contribute to renal functional and structural damage in malignant DOCA-salt SHR. Our results raise the possibility of renoprotective effects of ETA/B receptor blockers in certain forms of malignant hypertension.
authors.affiliation: First Department of Internal Medicine, Osaka City University Medical School, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kohno
authors.forename: K
authors.initials: K
authors.lastname: Yokokawa
authors.forename: K
authors.initials: K
authors.lastname: Yasunari
authors.forename: H
authors.initials: H
authors.lastname: Kano
authors.forename: M
authors.initials: M
authors.lastname: Minami
authors.forename: M
authors.initials: M
authors.lastname: Ueda
authors.forename: Y
authors.initials: Y
authors.lastname: Tatsumi
authors.forename: J
authors.initials: J
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D006830:Hydralazine / Q000627:therapeutic use; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012016:Reference Values; D012965:Sodium Chloride
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C088196:TAK 044; D006830:Hydralazine; D003900:Desoxycorticosterone; D012965:Sodium Chloride