Reduced epicardial vagal nerve density and impaired vagal control in a rat myocardial infarction–heart failure model

Delfiner, Matthew S.; Siano, John; Liu, Ying; Dedkov, Eduard I.; Zhang, Youhua

doi:10.1016/j.carpath.2016.10.003

Cited by 8 publications

(3 citation statements)

References 30 publications

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“…Delfiner et al (8) and others (1,41) have identified postganglionic cholinergic nerve fibers in the ventricular epicardium that stain with anti-choline acetyltransferase antibody, indicating stimulation limited infarct size in an animal model of I/R and, by 24 h, reduced macrophage/neutrophil infiltration at the site of injury. Given that these effects were partially blocked by a nonselective nicotinic receptor antagonist, further suggests that both pharmacologic and of mitochondria, we used cultured cells exposed to H/R to mimic cardiac I/R, and, as expected, intracellular ATP concentration was decreased significantly.…”

Section: Gts21 Increases Intracellular Atp Concentration After I/rmentioning

confidence: 97%

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Mavropoulos

Khan

Levy

et al. 2017

Mol Med

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Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury, and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically α-7 subtype (α7nAChR), in the myocardium remains unknown, which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure and rates of pressure development, without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconitine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion reduced infarct size by 42% (p < 0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p < 0.01). Flow cytometry of MitoTracker Red-stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21-treated compared with untreated I/R hearts. Intracellular adenosine triphosphate (ATP) concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p < 0.001), but significantly increased to normoxic levels with GTS21 treatment, which was abrogated by MLA pretreatment. Activation of stress-activated kinases JNK and p38MAPK was significantly reduced by GTS21 in I/R. We conclude that targeting myocardial α7nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size. online address: http://www.molmed.org

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Section: Gts21 Increases Intracellular Atp Concentration After I/rmentioning

confidence: 97%

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Mavropoulos

Khan

Levy

et al. 2017

Mol Med

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“…87 Earlier investigations suggested that postganglionic cholinergic nerve fibers in the ventricular epicardium are a local source of ACh. [88][89][90] Current knowledge highlights the importance of non-neuronal cholinergic signaling mechanisms that secrete ACh from cardiomyocytes and act in an autocrine/ paracrine manner to exert cardioprotection under stressful conditions. [90][91][92] In agreement with this, the ex vivo perfused heart preparation, which is isolated from peripheral immune and central nervous system inputs, demonstrated a reduction in infarct size and preservation of mitochondrial membrane potential in response to treatment with a selective a7nAChR agonist (GTS21).…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 99%

Cooling Down Inflammation in the Cardiovascular System via the Nicotinic Acetylcholine Receptor

Kaplan

Lakkis

El-Samadi

et al. 2023

Journal of Cardiovascular Pharmacology

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Inflammation is a major player in many cardiovascular diseases including hypertension, atherosclerosis, myocardial infarction, and heart failure. In many individuals, these conditions coexist and mutually exacerbate each other’s progression. The pathophysiology of these diseases entails the active involvement of both innate and adaptive immune cells. Immune cells that possess the α7 subunit of the nicotinic acetylcholine receptor (α7-nAChR) on their surface, have the potential to be targeted through both pharmacological and electrical stimulation of the cholinergic system. The cholinergic system regulates the inflammatory response to various stressors in different organ systems via systematically suppressing spleen-derived monocytes and chemokines, and locally improving immune cell function. Research on the cardiovascular system has demonstrated the potential for atheroma plaque stabilization and regression as favorable outcomes. Smaller infarct size and reduced fibrosis have been associated with improved cardiac function and a decrease in adverse cardiac remodeling. Furthermore, enhanced electrical stability of the myocardium can lead to a reduction in the incidence of ventricular tachyarrhythmia. Additionally, improving mitochondrial dysfunction and decreasing oxidative stress can result in less myocardial tissue damage caused by reperfusion injury. Restoring baroreflex activity and reduction in renal damage can promote blood pressure regulation and help counteract hypertension. Thus, the present review highlights the potential of nicotinic acetylcholine receptor activation as a natural approach to alleviate the adverse consequences of inflammation in the cardiovascular system.

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“…The sympathovagal imbalance often results in left ventricular dysfunction during the early stages of HF [ 30 ]. Decreased ventricular epicardial vagal nerve density has also been reported to potentially contribute to impaired cardiac vagal control in rats with HF [ 31 ]. For the treatment of HF, vagus nerve stimulation (VNS) has been shown to be beneficial for improving the autonomic balance in HF by enhancing vagal tone [ 32 ].…”

Section: Decreased Vagal Tone Is Associated With Increased Mortality mentioning

confidence: 99%

Pharmacological Modulation of Vagal Nerve Activity in Cardiovascular Diseases

Liu

Zhao

et al. 2018

Neurosci. Bull.

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Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal (parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit over-excitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients. Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and β-adrenergic receptors. In addition, vagomimetic drugs (such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.

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Reduced epicardial vagal nerve density and impaired vagal control in a rat myocardial infarction–heart failure model

Cited by 8 publications

References 30 publications

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Cooling Down Inflammation in the Cardiovascular System via the Nicotinic Acetylcholine Receptor

Pharmacological Modulation of Vagal Nerve Activity in Cardiovascular Diseases

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