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

Abstract

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

Collateral benefits of studying the vagus nerve in bioelectronic medicine

“…The growing insight into the inflammatory reflex and the receptor mechanisms mediating efferent vagus nerve anti-inflammatory output prompted new clinicallyoriented research. The anti-inflammatory and diseasealleviating effects of many α7nAChR agonists, including nicotine, GTS-21, choline, and PNU-282987 have been demonstrated in preclinical settings of sepsis, postoperative neuroinflammation, ischemia-reperfusion injury, obesity and type 2 diabetes, and other disorders (Parrish et al, 2008;Pavlov et al, 2007;Chatterjee et al, 2017;Mavropoulos et al, 2017;Terrando et al, 2011;Wang et al, 2011;Li et al, 2013;Yeboah et al, 2008;Hoover, 2017;Terrando & Pavlov, 2018) (Fig. 2).…”

The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports

“…82,83 Potential mechanisms for the antioxidative effects of AChE inhibitors are summarized and illustrated in both Figures 2 and 3. proteins.…”

“…76,78,82,132 As regards device therapy, VNS has been shown previously to reduce the infarct size and improve cardiac function in various animal models with cardiac I/R injury. To be specific, it has been shown that ACh, an mAChR agonist and an nAChR agonist provided cardioprotective effects in cardiac I/R injury in both in vivo and in vitro studies.…”

“…To be specific, it has been shown that ACh, an mAChR agonist and an nAChR agonist provided cardioprotective effects in cardiac I/R injury in both in vivo and in vitro studies. 76,78,82,132 As regards device therapy, VNS has been shown previously to reduce the infarct size and improve cardiac function in various animal models with cardiac I/R injury. 16,[133][134][135] In a heart transplantation model, Yuan and coworkers reported that donepezil decreased inflammatory cytokines, cardiac injury, fibrosis and apoptotic markers at 24 hours after heart transplantation.…”

Revisiting the Cardioprotective Effects of Acetylcholine Receptor Activation against Myocardial Ischemia/Reperfusion Injury

“…Moreover, a recent study reported that administration of GTS21, a selective α7nAChR agonist, significantly reduced the infarct size and improved left ventricular developed pressure (LVDP) and ±dP/dt compared with the control. The beneficial effects of GTS21 were blocked when co-administered with MLA, suggesting that GTS21 treatment decreased the infarct size and improved cardiac contractile function through the activation of α7nAChR [ 55 ]. In addition, Zhang et al have also demonstrated that the infarct size in mice hearts pretreated with electroacupuncture at the Neiguan acupoint (PC6) was significantly reduced compared with the control [ 8 ].…”