Pathophysiological roles of endothelin-1 in Dahl salt-sensitive hypertension.
The purpose of the present experiment was to study the pathophysiological roles of endothelin-1 (ET-1) in salt-sensitive hypertension with the use of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. PreproET-1 mRNA expression was determined by reverse transcription-polymerase chain reaction. In the kidney, expression of preproET-1 mRNA was greater in DS rats on a normal salt diet compared with DR rats of the same age. In DS rats, the level of preproET-1 mRNA expression in kidney had a significant correlation with systolic blood pressure. The expression of preproET-1 mRNA in aorta and kidney was increased by 3-week high salt intake in DS rats but not in DR rats. Expression of preproET-1 mRNA and ET-1 levels in left ventricle was exaggerated by high salt intake in DS rats. However, there was no significant difference in plasma ET-1 levels between DS and DR rats regardless of salt intake. Pressor response curves for ET-1 in DS rats with or without high salt intake were significantly shifted to the left compared with those in DR rats. A single oral dose (3 to 10 mg/kg) of J-104132 (L-753 037), a potent, orally active mixed endothelin A and B (ET(A)/ET(B)) receptor antagonist, reduced blood pressure to normotensive levels in DS rats with high salt intake, and its action was maintained for >/=24 hours. In DS rats with normal salt intake, J-104132 (10 mg/kg) slightly but significantly decreased blood pressure. DR rats did not show obvious depressor responses to J-104132 (10 mg/kg) regardless of salt intake. These results suggest that ET-1 acts as one of the pathophysiological factors in the development and maintenance of salt-sensitive hypertension, and a mixed ET(A)/ET(B) receptor antagonist could be useful in the treatment for salt-sensitive hypertension.
Ikeda
T
T
Department of Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan.
Ohta
H
H
Okada
M
M
Kawai
N
N
Nakao
R
R
Siegl
P K
PK
Kobayashi
T
T
Maeda
S
S
Miyauchi
T
T
Nishikibe
M
M
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011311:Pressoreceptors / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016277:Ventricular Function, Left
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C119319:J 104132