Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung.
The present study aimed to investigate the effects of olmesartan, an antagonist for angiotensin II receptor type 1(AT1), on the activation of extracellular signal-regulated kinases (ERK)1/2, tissue remodeling, and pro-inflammatory signals in the right ventricle and lung of mice during the early phase of hypobaric hypoxia. Phosphorylation of ERK1/2 in both tissue types in response to hypoxia peaked at 1-3 days, and declined rapidly in the right ventricle, whereas in the lung it was sustained for at least 8 days. Upregulation of angiotensinogen mRNA was observed in the hypoxic lung at 4-9 days, but not in the hypoxic right ventricle and pulmonary artery. Olmesartan inhibited the hypoxia-induced phosphorylation of ERK1/2 in the lung, but not in the right ventricle. Neither right ventricular hypertrophy nor the thickening of the intrapulmonary arterial wall was ameliorated by olmesartan. However, this drug inhibited the expression of the mRNA for angiotensinogen and several pro-inflammatory factors, including interleukin-6 and inducible nitric oxide synthase in the hypoxic lung. These results suggest that olmesartan blocks a potential positive feedback loop of the angiotensin II-AT1 receptor system, which may lead to attenuate pro-inflammatory signals in the mouse lung, that are associated with hypoxic pulmonary hypertension, without inducing any appreciable effects on the compensatory cardiopulmonary hypertrophy at an early phase of exposure to a hypobaric hypoxic environment.
Tanabe
Yoshiyuki
Y
Department of Cellular and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi, Shizuoka, 422-8526, Japan.
Morikawa
Yuki
Y
Kato
Takao
T
Kanai
Satoshi
S
Watakabe
Taichi
T
Nishijima
Ami
A
Iwata
Hijiri
H
Isobe
Kaori
K
Ishizaki
Mayumi
M
Nakayama
Koichi
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000808:Angiotensinogen / Q000187:drug effects / Q000235:genetics; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia; D007093:Imidazoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D000068557:Olmesartan Medoxomil; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D018836:Inflammation Mediators; D012333:RNA, Messenger; D013777:Tetrazoles; D000808:Angiotensinogen; D000068557:Olmesartan Medoxomil; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3