Antishock effect of anisodamine involves a novel pathway for activating α7 nicotinic acetylcholine receptor*

Liu, Chong; Shen, Fu‐Ming; Le, Yingying; Kong, Yan; Liu, Xia; Cai, Guo-Jun; Chen, Alex F.; Su, Ding‐Feng

doi:10.1097/ccm.0b013e31819598f5

Cited by 63 publications

(62 citation statements)

References 27 publications

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“…In cardiovascular system, the α7nAChR was reported as an important protector in myocardial ischemia/reperfusion injury [9], stroke [10], atherosclerosis [11] and hypertension [12,13]. Our group previously showed that activation of α7nAChR protects against lipopolysaccharide-induced septic shock via inhibiting release of inflammatory cytokines [14]. We also demonstrated that downregulation of α7nAChR might contribute to the development of end organ damage through inducing cardiovascular inflammation in both genetic and experimental hypertension [12,13].…”

Section: Introductionmentioning

confidence: 99%

Activation of a7 Nicotinic Acetylcholine Receptor Protects Against Oxidant Stress Damage Through Reducing Vascular Peroxidase-1 in a JNK Signaling-Dependent Manner in Endothelial Cells

Zhao

Xin

et al. 2014

Cell Physiol Biochem

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Aim: Alpha7 nicotinic acetylcholine receptor (α7nAChR), a subtype of nAChR regulating neurotransmission in central nervous system, is an essential regulator of cholinergic anti-inflammatory pathway in periphery. The present study was to determine the effects of activation of α7nAChR on oxidant stress-induced injury in endothelial cells. Methods: Cultured human umbilical vein endothelial cells were treated with H₂O₂ (400 µM) or H₂O₂ plus PNU-282987 (10 µM). Cell viability and membrane integrity were measured. Annexin V + PI assay, immunoblotting of bcl-2, bax and cleaved capase-3, and immunofluorescence of apoptosis inducing factor (AIF) were performed to evaluate apoptosis. Protein expression of vascular peroxidase-1 (VPO-1) and phosphor-JNK were measured by immunoblotting. Results: Activation of α7nAChR by a selective agonist PNU-282987 prevented H₂O₂-indced decrease of cell viability and increase of lactate dehydrogenase release. Activation of α7nAChR markedly reduced cell apoptosis and intracellular oxidative stress level. Moreover, activation of α7nAChR reduced H₂O₂-induced VPO-1 protein upregulation and JNK1/2 phosphorylation. The inhibitory effect of α7nAChR activation on VPO-1 was blocked by JNK inhibitor SP600125. In addition, pretreatment of α7nAChR antagonist methyllycaconitine blocked the cytoprotective effect of PNU-282987. Conclusion: These results provide the first evidence that activation of α7nAChR protects against oxidant stress-induced damage by suppressing VPO-1 in a JNK signaling pathway-dependent manner in endothelial cells.

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Section: Introductionmentioning

confidence: 99%

Activation of a7 Nicotinic Acetylcholine Receptor Protects Against Oxidant Stress Damage Through Reducing Vascular Peroxidase-1 in a JNK Signaling-Dependent Manner in Endothelial Cells

Zhao

Xin

et al. 2014

Cell Physiol Biochem

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“…However, the molecular mechanisms of these effects remain unclear [4,5] . Recently, a study conducted in this laboratory demonstrated that the anti-shock effects of anisodamine occur mainly via activation of the α7 nicotinic acetylcholine receptor (α7nAChR) [6] .…”

Section: Introductionmentioning

confidence: 99%

“…Our previous studies have shown that anisodamine blocks muscarinic receptors and promotes increased endogenous acetylcholine binding to the α7nAChR [6] .…”

Section: Introductionmentioning

confidence: 99%

Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors

Sun

Zhang

et al. 2012

Acta Pharmacol Sin

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Aim: To evaluate the anti-effects of anisodamine and neostigmine in animal models of endotoxic and hemorrhagic shock. Methods: Kunming mice were injected with lipopolysaccharide (LPS 30 mg/kg, ip) to induce endotoxic shock. Anisodamine (12.5, 25, and 50 mg/kg, ip) and neostigmine (12.5, 25, and 50 μg/kg, ip) were administered immediately after LPS injection. Survival rate was monitored, and the serum levels of TNF-α and IL-1β were analyzed using ELISA assays. The effects of anisodamine and neostigmine were also examined in α7 nicotinic acetylcholine receptor (α7 nAChR) knockout mice with endotoxic shock and in Beagle dogs with hemorrhagic shock. Results: In mice with experimental endotoxemia, combined administration of anisodamine and neostigmine significantly increased the survival rate and decreased the serum levels of inflammatory cytokines, as compared to those produced by either drug alone. The antishock effect of combined anisodamine and neostigmine was abolished in α7 nAChR knockout mice. On the other hand, intravenous injection of the combined anisodamine and neostigmine, or the selective α7 nAChR agonist PNU282987 exerted similar anti-shock effects in dogs with hemorrhagic shock. Conclusion:The results demonstrate that combined administration of anisodamine and neostigmine produces significant anti-shock effects, which involves activation of α7 nAChRs.

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“…10 The anti-inflammatory actions of vagal efferent activity appear to be mediated chiefly by acetylcholine (ACh) acting at the ␣7 nicotinic acetylcholine receptor (␣7nAChR). 11,[13][14][15] The vesicular acetylcholine transporter (VAChT) mediates the loading of ACh into secretory organelles in neurons, thereby making ACh available for release. 16,17 Thus, if impairment of cholinergic antiinflammatory pathways contributes to development of EOD during hypertension, then dysfunction of the ␣7nAChR and/or the VAChT seems likely.…”

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Dysfunction of the Cholinergic Anti-Inflammatory Pathway Mediates Organ Damage in Hypertension

et al. 2011

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Abstract-Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the ␣7 nicotinic acetylcholine receptor (␣7nAChR) in inflammation has recently been identified. We tested the hypothesis that ␣7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the ␣7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and ␣7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-␣, interleukin-1␤, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the ␣7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor B. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in ␣7nAChR Ϫ/Ϫ mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension. (Hypertension. 2011;57:298-307.) • Online Data Supplement Key Words: acetylcholine Ⅲ ␣7 nicotinic acetylcholine receptor Ⅲ inflammation Ⅲ hypertension Ⅲ end-organ damage H ypertension is a major risk factor for myocardial infarction, heart failure, stroke, and kidney dysfunction. Endorgan damage (EOD), including cardiac hypertrophy and myocyte dysfunction, vascular remodeling, and renal lesions, is a crucial mediatory link between hypertension and the development of these cardiovascular events. 1 Therefore, a better understanding of the mechanisms leading to hypertensive EOD could provide new avenues for prevention of cardiovascular events. Inflammation is very important in the genesis and development of EOD. 2,3 Furthermore, the reninangiotensin system can contribute to EOD, at least partly by promoting inflammation. 4 -7 However, cardiovascular inflammation and EOD can also occur without renin-angiotensin system activation, 8 so other mechanisms must also operate.Recent evidence indicates that neuronal 9 -11 cholinergic systems influence inflammatory responses by controlling the release of tumor necrosis factor (TNF)-␣, interleukin-(⌱L)-1␤, and IL-6 and that nonneuronal acetylcholine synthesis and rele...

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Antishock effect of anisodamine involves a novel pathway for activating α7 nicotinic acetylcholine receptor*

Abstract: These findings demonstrate that the antishock effect of anisodamine is intimately linked to alpha7nAChR-dependent anti-inflammatory pathway.

Cited by 63 publications

References 27 publications

Activation of a7 Nicotinic Acetylcholine Receptor Protects Against Oxidant Stress Damage Through Reducing Vascular Peroxidase-1 in a JNK Signaling-Dependent Manner in Endothelial Cells

Activation of a7 Nicotinic Acetylcholine Receptor Protects Against Oxidant Stress Damage Through Reducing Vascular Peroxidase-1 in a JNK Signaling-Dependent Manner in Endothelial Cells

Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors

Dysfunction of the Cholinergic Anti-Inflammatory Pathway Mediates Organ Damage in Hypertension

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