Blockade Of Muscarinic Receptors Research Articles

HIV-derived Proteins induce Hypertension, Sympatho-activation, and neuroinflammation via T cell-dependent mechanisms

Combination antiretroviral therapy (cART) has markedly increased life expectancy in people living with HIV (PLWH) and induced a switch in the cause of death from opportunistic diseases to cardiovascular disease (CVD). CVD is currently the leading cause of death in PLWH and hypertension, the primary risk factor for CVD, presents in more than 65% of them. However, the mechanisms whereby hypertension develops in PLWH remain unknown. In PLWH on cART, T lymphocytes (T cells) remain a viral reservoir for HIV and continue to secrete viral proteins. Viral proteins remain in circulation and are expressed in the central nervous system. Herein, we tested the hypothesis that expression of HIV-derived proteins increases blood pressure (BP), induces sympatho-activation and inflammation of the central nervous system. We utilized the Tg26 mouse model which expresses 7/9 viral proteins. Quantitative PCR analysis of viral protein expression showed that Tat, gp120, Nef, Vif, and Vpr are primarily expressed in spleen, lung, and brain tissues in Tg26 mice. Morphometric analysis revealed slight but significant increases and decreases in lean mass and fat weights respectively in Tg26. Flow cytometry analysis showed no reduction in CD4+ T cells in Tg26 mice indicating that this mouse model does not progress to AIDS and reproduce the conditions of virally suppressed PLWH. Blood pressure (BP) measurement via telemetry revealed a hypertensive phenotype in male and female Tg26 mice. Hypertension was associated with a larger drop in BP in response to ganglionic blockade but no alterations in heart rate responses to muscarinic and β-adrenergic receptor blockade in Tg26 mice, indicating that viral proteins expression increases neurogenic control of BP but did not alter cardiac autonomic control. β-adrenergic receptor blockade did not reduce BP in Tg26 mice. Tg26 mice also display increased aortic vasoconstriction to phenylephrine. To test the contribution of T cells in BP regulation and sympatho-activation, mice were subjected to a CTLA-4 inhibitor, abatacept, which inhibits T cell activation. Abatacept treatment significantly reduced BP, sympatho-activation, and phenylephrine constriction in Tg26 mice with no effects on wild-type mice. To determine whether the increase in sympatho-activation involves central inflammation, inflammatory cytokines and T cell markers levels were measured in the brain. Levels of pro-inflammatory cytokines including IL-1α, TNFα, IL-6, and CCL2 were increased in the brain of Tg26 mice as well as levels of the T-cell marker GATA3. Altogether, our data shows that the expression of HIV-derived proteins increases BP, sympatho-activation, and vascular adrenergic contractility via T cell-dependent mechanisms likely through central mechanisms involving neuro-inflammation. R01HL147639-01A1, R01HL15526501 and 19EIA34760167 (E.J.B). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nucleus accumbens core acetylcholine receptors modulate the balance of flexible and inflexible cue-directed motivation

Sign-tracking is a conditioned response where animals interact with reward-predictive cues due to the cues having motivational value, or incentive salience. The nucleus accumbens core (NAc) has been implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum has been attributed to both incentive motivation and behavioral flexibility. Here, we demonstrate a role for NAc ACh receptors in the flexibility of sign-tracking. Sign-tracking animals were exposed to an omission contingency, in which vigorous sign-tracking was punished by reward omission. Animals rapidly adjusted their behavior, but they maintained sign-tracking in a less vigorous manner that did not cancel reward. Within this context of sign-tracking being persistent yet flexible in structure, blockade of NAc nicotinic receptors (nAChRs) led to a persistence in the initial sign-tracking response during omission followed by a period of change in the makeup of sign-tracking, whereas blockade of muscarinic receptors (mAChRs) oppositely enhanced the omission-related development of the new sign-tracking behaviors. Later, once omission learning had occurred, nAChR blockade uniquely led to reduced sign-tracking and elevated reward-directed behaviors instead. These results indicate that NAc ACh receptors have opposing roles in maintaining learned patterns of sign-tracking, with nAChRs having a special involvement in regulating the structure of the sign-tracking response.

Molecular Basis of Transglutaminase-2 and Muscarinic Cholinergic Receptors in Experimental Myopia: A Target for Myopia Treatment.

Myopia, a prevalent refractive error disorder worldwide, is characterized by the elongation of the eye, leading to visual abnormalities. Understanding the genetic factors involved in myopia is crucial for developing therapeutic and preventive measures. Unfortunately, only a limited number of genes with well-defined functionality have been associated with myopia. In this study, we found that the homozygous TGM2-deleted gene in mice protected against the development of myopia by slowing down the elongation of the eye. The effectiveness of gene knockdown was confirmed by achieving a 60 percent reduction in TGM-2 transcript levels through the use of TGM-2-specific small interfering RNA (siRNA) in human scleral fibroblasts (SFs). Furthermore, treating normal mouse SFs with various transglutaminase inhibitors led to the down-regulation of TGM-2 expression, with the most significant reduction observed with specific TGM-2 inhibitors. Additionally, the study found that the pharmacological blockade of muscarinic receptors also slowed the progression of myopia in mice, and this effect was accompanied by a decrease in TGM-2 enzyme expression. Specifically, mice with homozygous mAChR5, mAChR1, and/or mAChR4 and knockout mice exhibited higher levels of TGM-2 mRNA compared to mice with homozygous mAChR2 and three knockout mice (fold changes of 5.8, 2.9, 2.4, -2.2, and -4.7, respectively; p < 0.05). These findings strongly suggest that both TGM-2 and muscarinic receptors play central roles in the development of myopia, and blocking these factors could potentially be useful in interfering with the progression of this condition. In conclusion, targeting TGM-2 may have a beneficial effect regarding myopia, and this may also be at least partially be the mechanism of anti-muscarinic drugs in myopia. Further studies should investigate the interaction between TGM-2 and muscarinic receptors, as well as the changes in other extracellular matrix genes associated with growth during the development of myopia.

Altered autonomic control or coronary artery blood flow by the aortic body chemoreceptors in conscious normotensive and hypertensive sheep

Peripheral arterial chemoreceptors monitor the chemical composition of the blood. While, the carotid bodies located at the bifurcation of the common carotid arteries have been extensively studied. The physiological role of the aortic bodies located in the walls of the aortic arch remains relatively under-studied, and its role in hypertension is unexplored.We hypothesized that activation of the aortic bodies would increase coronary blood flow in the normotensive state and that the parasympathetic nerves to the heart would mediate this.Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one-clip model (HTN. n=6) and a sham-clipped normotensive group (Con. n=6). Unilateral renal clipping increased resting mean arterial pressure (Con: 84±5 vs HTN 115±6 mmHg). The aortic body chemoreceptors were stimulated by a bolus infusion of potassium cyanide (KCN; 10-30 μg/kg) into the left ventricle.Activation of the aortic bodies in the normotensive and hypertensive animals resulted in a significant increase in coronary blood flow ( P&lt;0.05, 2-way ANOVA, interaction effect), which was not different between groups. In normotensive sheep, the aortic body chemoreflex-mediated coronary vasodilation was attenuated by atropine infusion. Interestingly, the coronary vasodilation in hypertensive animals was not altered by the blockade of muscarinic receptors but was attenuated after propranolol infusion ( P&lt;0.05, interaction effect). Bilateral vagotomy is not possible in conscious animals; under anesthesia, the coronary blood flow response to aortic body stimulation was significantly attenuated in normotensive sheep. Neither atropine nor propranolol affected the aortic body chemoreflex meditated changes in either group's blood pressure, heart rate, or cardiac output. This data suggests that the aortic bodies play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension. Many patients with hypertension are on beta-blockers. Our finding indicates that the aortic bodies modulate coronary blood flow via a beta-adrenergic mechanism in hypertension, which may have important implications for regulating coronary blood flow during exertion in hypertensive patients. Work is supported by the Health Research Council (HRC) of New Zealand. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Muscarinic acetylcholine activity modulates cortical silent period, but not motor evoked potentials, during muscle contractions

This study used transcranial magnetic stimulation (TMS) to determine if muscarinic receptor blockade affects muscle responses during voluntary contractions. Motor evoked potentials (MEPs) were recorded from biceps brachii in 10 subjects (age: 23 ± 2) during 10%, 25%, 50%, 75%, and 100% maximal voluntary contractions (MVCs). Each contraction intensity was examined under non-fatigued and fatigued conditions. All measurements were obtained post-ingestion of 25 mg promethazine or placebo. MEP area and the duration of the TMS-evoked silent period (SP) were calculated for all contractions. No drug-related differences were detected for MEP area during non-fatigued or fatigued contractions. A main effect of drug was detected for the SP (p = 0.019) where promethazine increased SP duration by an average of 0.023 pm 0.015 s. This drug effect was only identified for the unfatigued contractions and not following the sustained fatiguing contractions (p = 0.105). The cholinergic system does not influence corticospinal excitability during voluntary muscle contractions, but instead affects neural circuits associated with the TMS-evoked SP. Given the prevalence of cholinergic properties in prescription and over-the-counter medications, the current study enhances our understanding of mechanisms that may contribute to motor side-effects.

Effect of the Hydroalcoholic Extract from the Leafy Stems of Waltheria indica L. (Malvaceae) on Acetylcholine and Barium Chloride-Induced Contractions on Isolated Rat Tracheal Tissue

A previous study has reported the interesting relaxant effect of the hydroalcoholic extract from Waltheria indica L. (Malvaceae) leafy stems, a plant with several therapeutic uses. The present study aimed to investigate the preventive effect of this plant using an ex vivo model of the rat trachea. Two agonists, acetylcholine (10-6 - 1.5×10-5 M) and barium chloride (10-5- 10-1 M) were used to induce contractions. The preventive effect was assessed on rat tracheal rings pretreated with hydroalcoholic extract (1.92 mg/mL), glibenclamide, atropine, and papaverine, all at 10 µM. Acetylcholine and barium chloride provoke contractions in a concentration-dependent manner, with a maximum contractile response of 3.953 ± 0.692 g and 2.999 ± 0.326 g, respectively. The EC50 values were 3.711 ± 0.823 µM and 9.502 ± 12.354 mM, respectively, for acetylcholine- and barium chloride-induced contraction. Glibenclamide caused a rightward shift of the acetylcholine-response curve, followed by a reduction of the maximum contraction (from 3.953 ± 0.692 g to 3. 116 ± 0.244 g). The hydroalcoholic extract, atropine, papaverine, and their combinations induced a complete suppression of the contractile response to acetylcholine (p &lt; 0.0001) and barium chloride (p &lt; 0.0001). The hydroalcoholic extract exhibited a potent relaxant effect comparable to that of atropine and papaverine. It can be concluded that the hydroalcoholic extract of W. indica can potently prevent acetylcholine-and barium chloride-induced contractions. The possible mechanisms by which the extract exerts its relaxant effect may involve the blockade of muscarinic receptors, the inhibition of phosphodiesterase activity, and/or the calcium channel.

Muscarinic receptor activation overrides boundary conditions on memory updating in a calcium/calmodulin-dependent manner.

Long-term memory storage is a dynamic process requiring flexibility to ensure adaptive behavioural responding in changing environments. Indeed, it is well established that memory reactivation can "destabilize" consolidated traces, leading to various forms of updating. However, the neurobiological mechanisms rendering long-term memories labile and modifiable remain poorly described. Moreover, boundary conditions, such as the age or strength of the memory, can reduce the likelihood of this destabilization; yet, intuitively, these most behaviourally influential of memories should also be modifiable under appropriate conditions. Here, we provide evidence that salient novelty at the time of memory reactivation promotes integrative updating of resistant object memories in rats. Furthermore, blockade of muscarinic acetylcholine receptors (mAChRs; with pirenzepine) or disruption of calcium/calmodulin (Ca2+/CaM) with KN-93, a Ca2+/CaM-binding molecule that inhibits calcium/calmodulin-dependent protein kinase II (CaMKII) activation, in perirhinal cortex (PRh) prevented novelty-induced destabilization and updating of resistant object memories. Finally, PRh M1 mAChR activation (with CDD-0102A) was sufficient to destabilize resistant object memories for updating, and this effect was blocked by KN-93, possibly via inhibition of CaMKII activity. Thus, mAChRs and activation of CaMKII appear to interact as part of a mechanism to override boundary conditions on resistant object memories to ensure integrative modification with novel information. These findings therefore have important implications for understanding the dynamic nature of long-term memory storage and potential treatments for conditions characterized by maladaptive and inflexible memories.

Astrocytes Reduce Store-Operated Ca2+ Entry in Microglia under the Conditions of an Inflammatory Stimulus and Muscarinic Receptor Blockade.

Inflammation and loss of cholinergic transmission are involved in neurodegenerative diseases, but possible interactions between them within neurons, astrocytes, and microglia have not yet been investigated. We aimed to compare store-operated Ca2+ entry (SOCE) in neurons, astrocytes, and microglia following cholinergic dysfunction in combination with (or without) an inflammatory stimulus and to investigate the effects of linalyl acetate (LA) on this process. We used the SH-SY5Y, U373, and BV2 cell lines related to neurons, astrocytes, and microglia, respectively. Scopolamine or lipopolysaccharide (LPS) was used to antagonize the muscarinic receptors or induce inflammatory responses, respectively. The concentration of intracellular Ca2+ was measured using Fura-2 AM. Treatment with scopolamine and LPS significantly increased SOCE in the neuron-like cells and microglia but not in the scopolamine-pretreated astrocytes. LA significantly reduced SOCE in the scopolamine-pretreated neuron-like cells and microglia exposed to LPS, which was partially inhibited by the Na+-K+ ATPase inhibitor ouabain and the Na+/Ca2+ exchanger (NCX) inhibitor Ni2+. Notably, SOCE was significantly reduced in the LPS plus scopolamine-pretreated cells mixed with astrocytes and microglia, with a two-fold increase in the applied number of astrocytes. LA may be useful in protecting neurons and microglia by reducing elevated SOCE that is induced by inflammatory responses and inhibiting the muscarinic receptors via Na+-K+ ATPase and the forward mode of NCX. Astrocytes may protect microglia by reducing increased SOCE under the conditions of inflammation and a muscarinic receptor blockade.

Atropine-functionalized gold nanoparticles binding to muscarinic receptors after passage across the intestinal epithelium.

Gold nanoparticles have a high potential to be a treatment of diseases by their specific drug delivery properties and multivalent receptor stimulation. For the present project, spherical gold nanoparticles were synthesized and functionalized with the muscarinic receptor antagonist atropine (Au-MUDA-AT NPs). The diameter of the gold core could precisely be controlled by using different synthetic methods and reducing agents resulting in functionalized gold nanoparticles with diameters ranging from 8 to 16 nm. The ability to interact with intestinal muscarinic receptors is size-dependent. When using intestinal chloride secretion induced by the stable acetylcholine derivative, carbachol, as read-out, the strongest inhibition, i.e. the most efficient blockade of muscarinic receptors, was observed with 13 nm sized Au-MUDA-AT NPs. Functional experiments indicate that Au-MUDA-AT NPs with a diameter of 14 nm are able to pass the intestinal mucosa in a time-dependent manner after administration to the intestinal lumen. For example, luminally administered Au-MUDA-AT NPs inhibited contractions of the small intestinal longitudinal muscle layer induced by electrical stimulation of myenteric neurons. A similar inhibition of basolateral epithelial receptors was observed after luminal administration of Au-MUDA-AT NPs when using carbachol-induced chloride secretion across the intestinal epithelium as a test system. Thus, Au-MUDA-AT NPs might be a therapeutic tool for the modulation of intestinal secretion and motility after oral application in the future.

The role of age-associated autonomic dysfunction in inflammation and endothelial dysfunction.

Aging of the cardiovascular regulatory function manifests as an imbalance between the sympathetic and parasympathetic (vagal) components of the autonomic nervous system (ANS). The most characteristic change is sympathetic overdrive, which is manifested by an increase in the muscle sympathetic nerve activity (MSNA) burst frequency with age. Age-related changes that occur in vagal nerve activity is less clear. The resting tonic parasympathetic activity can be estimated noninvasively by measuring the increase in heart rate occurring in response to muscarinic cholinergic receptor blockade; animal study models have shown this to diminish with age. Humoral, cellular, and neural mechanisms work together to prevent non-resolving inflammation. This review focuses on the mechanisms underlying age-related alternations in the ANS and how an imbalance in the ANS, evaluated by MSNA and heart rate variability (HRV), potentially facilitates inflammation when the homeostatic mechanisms between reflex neural circuits and the immune system are compromised, particularly the dysfunction of the cholinergic anti-inflammatory reflex. Physiologically, the efferent arm of this reflex acts via the [Formula: see text] 7 nicotinic acetylcholine receptors expressed in macrophages, monocytes, dendritic cells, T cells, and endothelial cells to curb the release of inflammatory cytokines, in which inhibition of NF‑κB nuclear translocation and activation of a JAK/STAT-mediated signaling cascade in macrophages and other immune cells are implicated. This reflex is likely to become less adequate with advanced age. Consequently, a pro-inflammatory state induced by reduced vagus output with age is associated with endothelial dysfunction and may significantly contribute to the development and propagation of atherosclerosis, heart failure, and hypertension. The aim of this review is to summarize the relationship between ANS dysfunction, inflammation, and endothelial dysfunction in the context of aging. Meanwhile, this review also attempts to describe the role of HRV measures as a predictor of the level of inflammation and endothelial dysfunction in the aged population and explore the possible therapeutical effects of vagus nerve stimulation.

Aortic Body Chemoreceptors Regulate Coronary Blood Flow in Conscious Control and Hypertensive Sheep.

Peripheral arterial chemoreceptors monitor the chemical composition of arterial blood and include both the carotid and aortic bodies (ABs). While the role of the carotid bodies has been extensively studied, the physiological role of the ABs remains relatively under-studied, and its role in hypertension is unexplored. We hypothesized that activation of the ABs would increase coronary blood flow in the normotensive state and that this would be mediated by the parasympathetic nerves to the heart. In addition, we determined whether the coronary blood flow response to stimulation of the ABs was altered in an ovine model of renovascular hypertension. Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one clip model (n=6) and a sham-clipped normotensive group (n=6). Activation of the ABs in the normotensive animals resulted in a significant increase in coronary blood flow, mediated, in part by a cholinergic mechanism since it was attenuated by atropine infusion. Activation of the ABs in the hypertensive animals also increased coronary blood flow (P<0.05), which was not different from the normotensive group. Interestingly, the coronary vasodilation in the hypertensive animals was not altered by blockade of muscarinic receptors but was attenuated after propranolol infusion. Taken together, these data suggest that the ABs play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension.

Blockade of M4 muscarinic receptors on striatal cholinergic interneurons normalizes striatal dopamine release in a mouse model of TOR1A dystonia

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is commonly used for the treatment of dystonia associated with TOR1A, otherwise known as DYT1 dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. We previously found that THP normalizes the deficit in striatal dopamine (DA) release in a mouse model of TOR1A dystonia (Tor1a+/ΔE knockin (KI) mice), revealing a plausible mechanism of action for this compound, considering that abnormal DA neurotransmission is consistently associated with many forms of dystonia. However, the mAChR subtype(s) that mediate the rescue of striatal dopamine release remain unclear. In this study we used a combination of pharmacological challenges and cell-type specific mAChR conditional knockout mice of either sex to determine which mAChR subtypes mediate the DA release-enhancing effects of THP. We determined that THP acts in part at M4 mAChR on striatal cholinergic interneurons to enhance DA release in both Tor1a+/+ and Tor1a+/ΔE KI mice. Further, we found that the subtype selective M4 antagonist VU6021625 recapitulates the effects of THP. These data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that subtype selective M4 mAChR antagonists may be effective therapeutics with fewer side effects than THP for the treatment of TOR1A dystonia.

Muscarinic receptors blockade and nitric oxide production contribute in the relaxant effect of Berberis vulgaris extract on rat tracheal smooth muscle

Common barberry, or Berberis vulgaris (Berberidaceae), has been shown to possess multiple pharmacological activities. The present study evaluated the relaxant effect of a hydroalcoholic extract of B. vulgaris on rat tracheal smooth muscle (TSM) as well as possible molecular mechanisms. TSM samples were stimulated by 10μM methacholine or 60mM potassium chloride (KCl), and the effects of cumulative concentrations of the extract (0.1, 0.4, 1.6, 6.5mg/mL) and of theophylline (0.2, 0.4, 0.6 and 0.8mM) were examined. To assess the possible mechanism(s) of the plant relaxant effect, this effect was also examined on tissue incubated with atropine, chlorpheniramine, propranolol, diltiazem, glibenclamide, indomethacin, ω-nitro-L-arginine methyl ester (L-NAME) and papaverine. The results showed concentration-dependent relaxant effects of B. vulgaris on non-incubated TSM contracted by KCl and methacholine (P<0.05 to P<0.001). There was no significant difference in the relaxant effects of B. vulgaris between non-incubated tissue and tissue incubated with chlorpheniramine, propranolol, indomethacin, diltiazem, glibenclamide or papaverine. However, the relaxant effects of 1.6 and 6.5mg/mL of B. vulgaris on tissue incubated with L-NAME and of 6.5mg/mL of the extract on tissue incubated with atropine were significantly lower than on non-incubated tissue (P<0.05). The EC50 value of B. vulgaris on tissue incubated with chlorpheniramine was significantly higher than the non-incubated TSM (P<0.05). A relatively effective relaxant effect of B. vulgaris comparable to that of theophylline was shown. Muscarinic receptor blockade and nitric oxide production have been suggested as possible mechanisms for the relaxant effect.

Effectiveness of glycopyrronium bromide in the treatment of small airway dysfunction: A retrospective study.

Glycopyrronium bromide has a quaternary ammonium structure and a low oral bioavailability, which reduces its systemic effects; it acts through a bronchodilating blockade of muscarinic receptors. The aim of this retrospective study was to analyze a possible relationship between the changes in the small airways and the efficacy of a bronchodilation with glycopyrronium bromide; exercise tolerance was also assessed, by performing the six-minute walking test. Forty-one patients were identified (23 females/18 males; mean age 66.82 ± 9.75 years), with a normal forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio of 77.45% ± 4.86%, a reduced forced mid-expiratory flow between 25% and 75% of forced vital capacity (FEF25-75) of 42.9% ± 10.5%, with an increased residual volume/total lung capacity ratio of 132.68% ± 6.41%, FEV1 1.85 ± 0.54 L, forced vital capacity 2.39 ± 0.71 L, airway resistance (sR tot) 168.18% ± 42.5%, total lung capacity 98.28% ± 8.9%, six-minute walking test distance 318.3 ± 36.6 m, modified British Medical Research Council dyspnea scale 1.48 ± 0.77. All patients were initiated with glycopyrronium bromide 50 μg/die and reassessed after 4 months. After the treatment with glycopyrronium bromide, a significant improvement was noted regarding forced vital capacity (p = 0.04), FEF25-75 (p < 0.001), sR tot (p < 0.001), residual volume/total lung capacity ratio (p < 0.001) with reduction of dynamic hyperinflation, the significant increase of the distance covered during the six-minute walking test (p < 0.001), and modified British Medical Research Council (p < 0.001) showed enhanced exercise tolerance. FEV1 improved, but the difference was not statistically significant. Small airway dysfunction is associated with bronchodilator responsiveness. Glycopyrronium bromide has proven to be capable of inducing favorable effects on lung hyperinflation and its functional and clinical consequences, with a decrease in dyspnea and an increase in exercise capacity. The use of anticholinergic drugs is useful in the management of small airway disease.

The role of adrenergic and muscarinic receptors in stress-induced cardiac injury.

Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24h) of rats induced the state which is similar TS in human: contracture damage of myofibrils, elevation of the serum creatine kinase MB level, increased 99mTc-pyrophosphate (99mTc-PYP) accumulation in the heart, QTc interval prolongation, and contractility dysfunction of the heart. Immobilization stress resulted in an increase in coronary blood flow. Emotional stress increased the serum catecholamine level. Blockade of β1-adrenergic receptor (AR) prevented stress-induced cardiac injury (SICI). Blockade of β2-AR aggravated stress-induced cardiac injury. Stimulation of β2-AR increased cardiac tolerance to stress. Inhibition of β3-AR, α1-AR had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravated SICI. Pretreatment with the selective β1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction, but recovery of cardiac contractility is not complete. There is indirect evidence that circulating catecholamines play an important role in SICI. Consequently, the activation of β1-AR plays a significant role in SICI. However, there are other receptors which are also involved in SICI and require further investigation.

Sulforaphane enhances long-term potentiation and ameliorate scopolamine-induced memory impairment

Increases in human life expectancy have led to increases in the prevalence of senile dementia and neurodegenerative diseases. This is a major problem because there are no curative treatments for these diseases, and patients with unmanaged cognitive and neurodegenerative symptoms experience many social problems. Sulforaphane is a type of organosulfur compound known as an isothiocyanate. It is derived from glucoraphanin, a compound found in cruciferous vegetables such as broccoli, brussels sprouts, and cabbages, via an enzymatic reaction that is triggered by plant damage (e.g., chewing). Sulforaphane exhibits activity against cancer, inflammation, depression, and severe cardiac diseases. It can also alleviate oxidative stress and neural dysfunction in the brain. However, there is insufficient knowledge about the electrophysiological and behavioral basis of the effects of sulforaphane on learning and memory. Therefore, we evaluated whether acute sulforaphane administration affected long-term potentiation (LTP) in organotypic cultured rat hippocampal tissues. We also measured the effect of sulforaphane on the performance of three behavioral tests, the Y-maze test, the passive avoidance test, and the Morris water maze, which assess short-term memory, avoidance memory, and short and long-term spatial memory, respectively. We found that sulforaphane increased the total field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after high frequency stimulation and attenuated scopolamine-induced interference of the fEPSP in the hippocampal CA1 area. Sulforaphane also restored cognitive function and inhibited memory impairment as indicated by the alleviation of the negative neurological effects of scopolamine, i.e, a lowered ratio of spontaneous alternation in the Y-maze, a reduced step-through latency in the passive avoidance test, and an increased navigation time in the Morris water maze. These results indicate that sulforaphane can effectively prevent the attenuation of LTP and cognitive abilities induced by cholinergic and muscarinic receptor blockade. Further research is warranted to explore the potential therapeutic and prophylactic utility of sulforaphane for improving learning and memory, especially in those suffering from neurodegenerative disorders.

Pulmonary Microcirculation during Experimental Pulmonary Thromboembolism under Conditions of Activation and Blockade of Muscarinic Acetylcholine Receptors.

Changes in pulmonary microcirculation were studied in isolated perfused rabbit lungs during modelling pulmonary thromboembolism under conditions of acetylcholine infusion against the background of treatment with M1 acetylcholine receptor blocker pirenzepine or blockade of muscarinic acetylcholine receptors with atropine. In the first case, the increase in pulmonary artery pressure was less pronounced than in case of atropine treatment. In response to pulmonary embolism after acetylcholine infusion against the background of pirenzepine pretreatment, the capillary hydrostatic pressure and postcapillary resistance did not change, while after atropine treatment, these parameters increased. In case of pulmonary embolism after acetylcholine infusion combined with selective blockade of M1 muscarinic acetylcholine receptors, the capillary filtration coefficient increased to a greater extent, than in the control and after blockade of muscarinic acetylcholine receptors.

The Role of Adrenergic Receptors, Muscarinic Receptors, Glucocorticoids, Reactive Oxygen Species in Stress‐Induced Cardiac Injury

Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that would be as close as possible to TS. We hypothesized that adrenergic receptors, muscarinic receptors, glucocorticoids, reactive oxygen species (ROS) can be involved in the development of stress-induced cardiac injury (SICI). It was established that immobilization of rats induced the state which is similar TS in human: increased 99mTc-pyrophosphate (99mTc-PP) accumulation in the heart, QTc interval prolongation, contractility dysfunction of the heart, elevation of the serum creatine kinase MB level. Immobilization stress induced an increase in coronary blood flow. Blockade of β1-adrenergic receptor (AR) prevents 99mTc-PP accumulation in the myocardium. Blockade of β2-AR aggravates SICI. Stimulation of β2-AR increased cardiac tolerance to stress. Inhibition of β3-AR, α1-AR, mineralocorticoid receptor and angiotensin AT1 receptor had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravates SICI. Inhibition of glucocorticoid receptor attenuated but not abolished SICI. Pretreatment with the selective β1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction but not recover cardiac contractility completely. It was established that ROS are not involved in SICI. It was obtained indirect evidence that circulated in blood catecholamines play an important role in SICI. Consequently, the activation of β1-AR plays an important role in SICI. However, there are other receptors which are also involved in SICI.

Effects of muscarinic and nicotinic receptors on contextual modulation in macaque area V1

Context affects the salience and visibility of image elements in visual scenes. Collinear flankers can enhance or decrease the perceptual and neuronal sensitivity to flanked stimuli. These effects are mediated through lateral interactions between neurons in the primary visual cortex (area V1), in conjunction with feedback from higher visual areas. The strength of lateral interactions is affected by cholinergic neuromodulation. Blockade of muscarinic receptors should increase the strength of lateral intracortical interactions, while nicotinic blockade should reduce thalamocortical feed-forward drive. Here we test this proposal through local iontophoretic application of the muscarinic receptor antagonist scopolamine and the nicotinic receptor antagonist mecamylamine, while recording single cells in parafoveal representations in awake fixating macaque V1. Collinear flankers generally reduced neuronal contrast sensitivity. Muscarinic and nicotinic receptor blockade equally reduced neuronal contrast sensitivity. Contrary to our hypothesis, flanker interactions were not systematically affected by either receptor blockade.

Neuromodulation of Persistent Activity and Working Memory Circuitry in Primate Prefrontal Cortex by Muscarinic Receptors

Neuromodulation by acetylcholine plays a vital role in shaping the physiology and functions of cerebral cortex. Cholinergic neuromodulation influences brain-state transitions, controls the gating of cortical sensory stimulus responses, and has been shown to influence the generation and maintenance of persistent activity in prefrontal cortex. Here we review our current understanding of the role of muscarinic cholinergic receptors in primate prefrontal cortex during its engagement in the performance of working memory tasks. We summarize the localization of muscarinic receptors in prefrontal cortex, review the effects of muscarinic neuromodulation on arousal, working memory and cognitive control tasks, and describe the effects of muscarinic M1 receptor stimulation and blockade on the generation and maintenance of persistent activity of prefrontal neurons encoding working memory representations. Recent studies describing the pharmacological effects of M1 receptors on prefrontal persistent activity demonstrate the heterogeneity of muscarinic actions and delineate unexpected modulatory effects discovered in primate prefrontal cortex when compared with studies in rodents. Understanding the underlying mechanisms by which muscarinic receptors regulate prefrontal cognitive control circuitry will inform the search of muscarinic-based therapeutic targets in the treatment of neuropsychiatric disorders.