TY - JOUR
T1 - Brain AT1 receptor activates the sympathetic nervous system through toll-like receptor 4 in mice with heart failure
AU - Ogawa, Kiyohiro
AU - Hirooka, Yoshitaka
AU - Kishi, Takuya
AU - Sunagawa, Kenji
PY - 2011/11
Y1 - 2011/11
N2 - The activation of angiotensin II type 1 receptor (AT1R) in the brain plays a pivotal role in enhanced sympathetic drive in heart failure (HF). Activation of the AT1R in the brain produces oxidative stress and inflammation. Toll-like receptor 4 (TLR4) signaling in the brain induces the inflammatory cascade. We hypothesized that sympathoexcitation is mediated by the AT1R-activated TLR4 in the brainstem in HF. As a model of HF, the left coronary artery was ligated to induce a large myocardial infarction and subsequent chronic heart failure (CHF) in Institute of Cancer Research mice. On day 10 after the surgery, we started intracerebroventricular infusion of losartan (CHF-Los) or vehicle (CHF-Veh) via osmotic minipumps for 14 days. Expression level of the TLR4 in the brainstem was significantly higher in HF mice than in sham mice and significantly lower in CHF-Los mice than in CHF-Veh mice. Urinary norepinephrine excretion was significantly higher in HF mice than in sham mice and was significantly lower in CHF-Los than in CHF-Veh. Chronic intracerebroventricular infusion of angiotensin II increased the expression level of the second messenger of the TLR4. These results suggest that activation of the TLR4 via AT1R in the brainstem contributes to the sympathoexcitation probably due to the inflammation in the brain of the myocardial infarction-induced HF.
AB - The activation of angiotensin II type 1 receptor (AT1R) in the brain plays a pivotal role in enhanced sympathetic drive in heart failure (HF). Activation of the AT1R in the brain produces oxidative stress and inflammation. Toll-like receptor 4 (TLR4) signaling in the brain induces the inflammatory cascade. We hypothesized that sympathoexcitation is mediated by the AT1R-activated TLR4 in the brainstem in HF. As a model of HF, the left coronary artery was ligated to induce a large myocardial infarction and subsequent chronic heart failure (CHF) in Institute of Cancer Research mice. On day 10 after the surgery, we started intracerebroventricular infusion of losartan (CHF-Los) or vehicle (CHF-Veh) via osmotic minipumps for 14 days. Expression level of the TLR4 in the brainstem was significantly higher in HF mice than in sham mice and significantly lower in CHF-Los mice than in CHF-Veh mice. Urinary norepinephrine excretion was significantly higher in HF mice than in sham mice and was significantly lower in CHF-Los than in CHF-Veh. Chronic intracerebroventricular infusion of angiotensin II increased the expression level of the second messenger of the TLR4. These results suggest that activation of the TLR4 via AT1R in the brainstem contributes to the sympathoexcitation probably due to the inflammation in the brain of the myocardial infarction-induced HF.
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U2 - 10.1097/FJC.0b013e31822e6b40
DO - 10.1097/FJC.0b013e31822e6b40
M3 - Article
C2 - 21822148
AN - SCOPUS:80955142869
VL - 58
SP - 543
EP - 549
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
SN - 0160-2446
IS - 5
ER -