Effect of olmesartan on tissue expression balance between angiotensin II receptor and its inhibitory binding molecule.
We previously cloned a novel molecule interacting with angiotensin II (Ang II) type 1 receptor protein (ATRAP) and showed it to be an endogenous inhibitor of Ang II type 1 receptor signaling in cardiovascular cells. In this study, we tested a hypothesis that the balance of tissue expression of ATRAP and Ang II type 1 receptor is regulated in a tissue-specific manner during the development of hypertension and related cardiac hypertrophy. Concomitant with blood pressure increase and cardiac hypertrophy in spontaneously hypertensive rats, there was a constitutive decrease in the ratio of cardiac expression of ATRAP to Ang II type 1 receptor. However, treatment with olmesartan, an Ang II type 1 receptor-specific antagonist, either at a depressor or subdepressor dose, recovered the suppressed cardiac ATRAP to Ang II type 1 receptor ratio, which was accompanied by a decrease in Ang II type 1 receptor density, an inhibition of p38 mitogen-activated protein kinase activity, and a regression of cardiac hypertrophy. Furthermore, Ang II stimulation suppressed the ATRAP to Ang II type 1 receptor ratio with hypertrophic responses in both the cardiomyocytes and rat hearts. These findings show a tissue-specific regulatory balancing of the expression of ATRAP and Ang II type 1 receptor during the development of hypertension and cardiac remodeling and further suggest that the upregulation of the tissue ATRAP to Ang II type 1 receptor ratio may be one of the therapeutic benefits of olmesartan beyond its blood pressure-lowering effect.
Shigenaga
Atsu-ichiro
A
Department of Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan.
Tamura
Kouichi
K
Wakui
Hiromichi
H
Masuda
Shin-ichiro
S
Azuma
Koichi
K
Tsurumi-Ikeya
Yuko
Y
Ozawa
Motoko
M
Mogi
Masaki
M
Matsuda
Miyuki
M
Uchino
Kazuaki
K
Kimura
Kazuo
K
Horiuchi
Masatsugu
M
Umemura
Satoshi
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D004195:Disease Models, Animal; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C437965:olmesartan