Antihypertensive effect of a proteasome inhibitor in DOCA-salt hypertensive rats.
To search for a possible role for vascular proteasome in hypertension, we examined changes in proteasome level in aorta of deoxycorticosterone acetate (DOCA)-salt hypertensive rats and evaluated the antihypertensive effect of a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal (PSI). Two weeks after the start of DOCA-salt treatment, the rats, with systolic blood pressure being 154 +/- 5 mmHg, were randomly divided into two groups and were given PSI or its vehicle for 2 weeks. Vehicle-treated DOCA-salt rats developed marked hypertension after 4 weeks (198 +/- 9 mmHg), with increases in aortic proteasome activity and content. The systolic blood pressure was positively correlated with both the content and activity of aortic proteasome. The administration of PSI to DOCA-salt hypertensive rats suppressed the elevation of systolic blood pressure (144 +/- 4 mmHg), accompanied by decreases in aortic proteasome activity and content. These results suggest that proteasome production in vascular tissues is increased in DOCA-salt hypertensive rats, and that PSI exhibits antihypertensive effect in this experimental hypertensive model. Thus, the findings indicate the pathophysiological importance of increased vascular proteasome in the development of DOCA-salt hypertension.
Takaoka
M
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
Okamoto
H
H
Ito
M
M
Nishioka
M
M
Kita
S
S
Matsumura
Y
Y
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000201:enzymology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D003900:Desoxycorticosterone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex