Olmesartan ameliorates insulin sensitivity by modulating tumor necrosis factor-alpha and cyclic AMP in skeletal muscle.
We have reported that tumor necrosis factor (TNF)-alpha in skeletal muscle is one of the determinants of insulin resistance and that the renin-angiotensin system may be related to the regulation of TNF-a in skeletal muscle. Recent studies have suggested the involvement of cyclic adenosine monophosphate (cAMP) in the regulation of TNF-a in vascular smooth muscle cells or monocytes. The aim of this study was to determine the relationship between cAMP and TNF-a in skeletal muscle in connection with the renin-angiotensin system. Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow for 6 weeks. For the last 2 weeks of a 6-week period, the rats were treated with a vehicle or with an angiotensin II type 1 receptor antagonist (olmesartan medoxomil, 0.1 mg/kg/day). TNF-alpha levels in the soleus muscle were significantly higher and cAMP levels in the soleus muscle were significantly lower in fructose-fed rats than in control rats. Olmesartan increased cAMP and reduced TNF-a simultaneously in fructose-fed rats. There was a significant negative correlation between levels of cAMP and TNF-alpha. Moreover, a cAMP analogue reduced TNF-a levels in the soleus muscle. These results indicate that the increase in TNF-alpha via suppression of cAMP may affect the induction of insulin resistance. In addition, the facts that olmesartan increased cAMP and decreased TNF-alpha suggest that a part of the TNF-alpha regulation by angiotensin II might consist of modulation of cAMP through Gi protein activation in skeletal muscle.
Yamaguchi
Koichi
K
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Ura
Nobuyuki
N
Murakami
Hideyuki
H
Togashi
Nobuhiko
N
Hyakukoku
Masaya
M
Higashiura
Katsuhiro
K
Shimamoto
Kazuaki
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002118:Calcium; D000242:Cyclic AMP / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C437965:olmesartan; D000242:Cyclic AMP; D002118:Calcium