Propofol-induced Depression of Cultured Rat Ventricular Myocytes Is Related to the M2-acetylcholine Receptor–NO–cGMP Signaling Pathway 

1999 ◽  
Vol 91 (6) ◽  
pp. 1712-1712 ◽  
Author(s):  
Shuji Yamamoto ◽  
Shin Kawana ◽  
Atsushi Miyamoto ◽  
Hideyo Ohshika ◽  
Akiyoshi Namiki
Keyword(s):  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Ventricular Myocytes ◽  
Receptor Activation ◽  
Muscarinic Acetylcholine Receptors ◽  
No Production ◽  
Dependent Manner ◽  
Rat Ventricular Myocytes ◽  
Muscarinic Acetylcholine ◽  
Nitrite Production

Background It is well-known that propofol sometimes causes bradycardia or asystole during anesthesia; however, the direct effect of propofol on the myocardium remains unclear. Previous reports showed the contribution of muscarinic acetylcholine receptors to propofol-induced bradycardia. Conversely, it was suggested recently that nitric oxide (NO) plays an important role in mediating the effect of vagal stimulation in the autonomic regulation of the heart. Therefore, the authors investigated the effects of propofol on spontaneous contraction and NO production in cultured rat ventricular myocytes. Methods The authors measured chronotropic responses of cultured rat ventricular myocytes induced by propofol stimulation with a sensor, a fiber-optic displacement measurement instrument. The authors also quantitatively analyzed NO metabolite production in cultured myocytes by measuring the levels of nitrite and nitrate in a high-performance liquid chromatography reaction system. The influence of propofol on muscarinic acetylcholine receptors of myocyte membranes was also measured with a competitive binding assay using [3H]quinuclidinyl benzilate ([3H]QNB). Results Propofol caused negative chronotropy in a dose-dependent manner. Propofol (IC50) also caused the enhancement of nitrite production in cultured myocytes. Eighty percent of the enhancement of nitrite production induced by propofol (IC50) stimulation was abolished by pretreatment with atropine, methoctramine, or N(G)-monomethyl-L-arginine acetate (L-NMMA). The negative chronotropy induced by propofol (IC50) stimulation was reduced to 40-50% by pretreatment with atropine, methoctramine, L-NMMA, or 1H[1,2,4]oxadiazolo[4,3-alpha]quanoxalin-1-one, a selective inhibitor of guanylyl cyclase. Propofol displaced [3H]QNB binding to the cell membrane of myocytes in a concentration-dependent manner. Conclusion These results suggest that the negative chronotropy induced by propofol is mediated in part by M2-acetylcholine receptor activation, which involves the enhancement of NO production in cultured rat ventricular myocytes.

scholarly journals Role of Muscarinic Acetylcholine Receptors in Breast Cancer: Design of Metronomic Chemotherapy

2019 ◽  
Vol 14 (2) ◽  
pp. 91-100 ◽  
Author(s):  
María E. Sales ◽  
Alejandro J. Español ◽  
Agustina R. Salem ◽  
Paola M. Pulido ◽  
Y. Sanchez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Acetylcholine Receptors ◽  
Metronomic Chemotherapy ◽  
Chemotherapeutic Agents ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Dependent Manner ◽  
Muscarinic Agonists ◽  
Muscarinic Acetylcholine

Background: muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies. Methods: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment. The characteristics of screened papers were described using the mentioned conceptual framework. Results: Muscarinic antagonists and agonists have been assayed for the treatment of tumors established in lung, brain and breast with beneficial effects. We described an up-regulation of mAChRs in mammary tumors and the lack of expression in non-tumorigenic breast cells and normal mammary tissues. We and others demonstrated that muscarinic agonists can trigger anti-tumor actions in a dose-dependent manner on tumors originated in different organs like brain or breast. At pharmacological concentrations, they exert similar effects to traditional chemotherapeutic agents. Metronomic chemotherapy refers to the administration of anti-cancer drugs at low doses with short intervals among them, and it is a different regimen applied in cancer treatment reducing malignant growth and angiogenesis, and very low incidence of adverse effects. Conclusion: The usage of subthreshold concentrations of muscarinic agonists combined with conventional chemotherapeutic agents could be a promising tool for breast cancer therapy.

scholarly journals Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4)

2015 ◽  
Vol 20 (7) ◽  
pp. 858-868 ◽  
Author(s):  
Emery Smith ◽  
Peter Chase ◽  
Colleen M. Niswender ◽  
Thomas J. Utley ◽  
Douglas J. Sheffler ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptor ◽  
Muscarinic Acetylcholine Receptors ◽  
Response Analysis ◽  
Allosteric Modulators ◽  
Muscarinic Acetylcholine ◽  
Single Well ◽  
Well Assay ◽  
Receptor Modulators

Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer’s disease and other disorders involving impaired cognitive function. In an attempt to identify orthosteric and allosteric modulators of the muscarinic acetylcholine receptor M4 (M4), we developed a homogenous, multiparametric, 1536-well assay to measure M4 receptor agonism, positive allosteric modulation (PAM), and antagonism in a single well. This assay yielded a Z′ of 0.85 ± 0.05 in the agonist, 0.72 ± 0.07 in PAM, and 0.80 ± 0.06 in the antagonist mode. Parallel screening of the M1 and M5 subtypes using the same multiparametric assay format revealed chemotypes that demonstrate selectivity and/or promiscuity between assays and modalities. This identified 503 M4 selective primary agonists, 1450 PAMs, and 2389 antagonist hits. Concentration-response analysis identified 25 selective agonists, 4 PAMs, and 41 antagonists. This demonstrates the advantages of this approach to rapidly identify selective receptor modulators while efficiently removing assay artifacts and undesirable compounds.

scholarly journals Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-parkinsonian and anti-dystonic efficacy

2020 ◽  
Author(s):  
Mark S. Moehle ◽  
Aaron M. Bender ◽  
Jonathan W. Dickerson ◽  
Daniel J. Foster ◽  
Yuping Donsante ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Acetylcholine Receptor ◽  
Movement Disorders ◽  
Intracellular Signaling ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptor ◽  
Muscarinic Acetylcholine Receptors ◽  
Muscarinic Acetylcholine ◽  
Selective Antagonists

AbstractNon-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

scholarly journals Age-Dependent Effects of Conditioning on Cholinergic and Vasopressin Systems in the Rat Suprachiasmatic Nucleus

2003 ◽  
Vol 384 (5) ◽  
pp. 729-736 ◽  
Author(s):  
B. A. M. Biemans ◽  
E. A. Van der Zee ◽  
S. Daan
Keyword(s):  
Fear Conditioning ◽  
Suprachiasmatic Nucleus ◽  
Acetylcholine Receptors ◽  
Circadian System ◽  
Muscarinic Acetylcholine Receptors ◽  
Dependent Manner ◽  
Aged Rats ◽  
Muscarinic Acetylcholine ◽  
Young Rats ◽  
Age Dependent

Abstract Active shock avoidance was used to explore the impact of behavioural stimulation on the neurochemistry of the suprachiasmatic nucleus. We have found previously that the expression of muscarinic acetylcholine receptors in the suprachiasmatic nucleus of young rats was significantly enhanced 24 hours after fear conditioning. Here, we investigated whether this observation is age-dependent. We used 26 month-old Wistar rats with a deteriorated circadian system, and compared them with young rats (4 months of age) with an intact circadian system. Vasopressin, representing a major output system of the suprachiasmatic nucleus, was studied in addition to muscarinic receptors. Young rats showed a significant increase in immunostaining for muscarinic acetylcholine receptors 24 h after training, corroborating earlier observations. Aged rats did not show such an increase. In contrast, aged rats did show an increase in vasopressin immunoreactivity 24 h after fear conditioning, both at the level of content and cell number, while young rats did not reveal a significant rise. Thus, it seems that these two neurochemical systems in the suprachiasmatic nucleus are regulated independently. The results further demonstrate that the circadian pacemaker is influenced by fear conditioning in an age-dependent manner.

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