scholarly journals Postjunctional M2 Muscarinic Receptors Augment Neurally -Mediated Cholinergic Contractions Of Murine Airway Smooth Muscle

Function ◽  
2021 ◽  
Author(s):  
Sean M Ward
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
M2 Muscarinic Receptors

Role of M2 muscarinic receptors in airway smooth muscle contraction

Life Sciences ◽  
1999 ◽  
Vol 64 (6-7) ◽  
pp. 443-448 ◽  
Author(s):  
Carol A. Hirshman ◽  
Boris Lande ◽  
Thomas L. Croxton
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Smooth Muscle Contraction ◽  
M2 Muscarinic Receptors

A Mechanism for Rapacuronium-induced Bronchospasm

2003 ◽  
Vol 98 (4) ◽  
pp. 906-911 ◽  
Author(s):  
Edmund Jooste ◽  
Farrah Klafter ◽  
Carol A. Hirshman ◽  
Charles W. Emala
Keyword(s):  
Smooth Muscle ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Radioligand Binding ◽  
Neuromuscular Blocking ◽  
Parasympathetic Nerve ◽  
Release Of Acetylcholine ◽  
M3 Muscarinic Receptor ◽  
M2 Muscarinic Receptors

Background A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction. Methods Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors. Results Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean +/- SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 +/- 1.5 microm (n = 6); M3 muscarinic receptor, 77.9 +/- 11 microm (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants. Conclusions Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor-mediated airway smooth muscle constriction.

Direct and indirect actions of histamine on airway smooth muscle in guinea pigs

1984 ◽  
Vol 62 (6) ◽  
pp. 727-733 ◽  
Author(s):  
D. F. Biggs
Keyword(s):  
Smooth Muscle ◽  
Sodium Cromoglycate ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Guinea Pigs ◽  
The Other ◽  
Glossopharyngeal Nerve ◽  
Drug Induced ◽  
Afferent Pathways

Studies in guinea pigs showed that some forms of drug-induced bronchospasm are reflexogenic involving afferents in the glossopharyngeal nerve. At least two pathways appear to be involved. One pathway contains H1 receptors and is blocked by mepyramine and sodium cromoglycate (SCG), and its pharmacological characteristics are similar to those of active reflex vasodilation. The other appears to involve peripheral muscarinic receptors. The findings also indicate that SCG may act on efferent as well as afferent pathways.

Muscarinic Receptors and Control of Airway Smooth Muscle

1998 ◽  
Vol 158 (supplement_2) ◽  
pp. S154-S160 ◽  
Author(s):  
ALLISON D. FRYER ◽  
DAVID B. JACOBY
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
And Control

G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation

2004 ◽  
Vol 286 (2) ◽  
pp. L312-L319 ◽  
Author(s):  
J. K. L. Walker ◽  
R. R. Gainetdinov ◽  
D. S. Feldman ◽  
P. K. McFawn ◽  
M. G. Caron ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Muscle Relaxation ◽  
Receptor Activation ◽  
Smooth Muscle Relaxation ◽  
Airway Responses ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M2 muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene ( GRK5- /-) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5- /- and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from β2-adrenergic receptor activation were diminished in GRK5- /- mice. These data suggest that M2 muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5- /- mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease.

Muscarinic receptor reserve of airway smooth muscle and the response to isoproterenol

1990 ◽  
Vol 68 (3) ◽  
pp. 1017-1023
Author(s):  
J. M. Madison
Keyword(s):  
Smooth Muscle ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Important Determinant ◽  
Effective Concentration ◽  
Tracheal Smooth Muscle ◽  
Receptor Reserve ◽  
Force Transducers

It has been hypothesized that the muscarinic receptor reserve for contraction of airway smooth muscle is an important determinant of the potency with which isoproterenol relaxes submaximal muscarinic contractions. The goals of this study were to inactivate, with phenoxybenzamine, a fraction of the muscarinic receptors present in canine tracheal smooth muscle, and then to determine whether this decrease in muscarinic receptor reserve altered the potency with which isoproterenol relaxed submaximal muscarinic contractions. Strips of smooth muscle were suspended from force transducers in vitro and preincubated with either vehicle (untreated) or phenoxybenzamine (10(-5) M) for 30 min. For muscarinic contractions induced by carbachol that were approximately 70-80% of maximum, the half-maximally effective concentration of isoproterenol was 2.4 +/- 0.8 x 10(-7) M for untreated strips but 5.8 +/- 1.3 x 10(-9) M for strips treated with phenoxybenzamine (n = 6, P less than 0.05). We concluded that treatment with phenoxybenzamine increased the sensitivity of a submaximal muscarinic contraction to isoproterenol. The results support the hypothesis that the muscarinic receptor reserve for contraction is an important determinant of the potency with which isoproterenol relaxes submaximal muscarinic contractions.

scholarly journals Phosphorylation of the 27-kDa heat shock protein via p38 MAP kinase and MAPKAP kinase in smooth muscle

1997 ◽  
Vol 273 (5) ◽  
pp. L930-L940 ◽  
Author(s):  
Janice K. Larsen ◽  
Ilia A. Yamboliev ◽  
Lee A. Weber ◽  
William T. Gerthoffer
Keyword(s):  
Smooth Muscle ◽  
Stress Response ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein

The 27-kDa heat shock protein (HSP27) is expressed in a variety of tissues in the absence of stress and is thought to regulate actin filament dynamics, possibly by a phosphorylation/dephosphorylation mechanism. HSP27 has also been suggested to be involved in contraction of intestinal smooth muscle. We have investigated phosphorylation of HSP27 in airway smooth muscle in response to the muscarinic agonist carbachol. Carbachol increased32P incorporation into canine tracheal HSP27 and induced a shift in the distribution of charge isoforms on two-dimensional gels to more acidic, phosphorylated forms. The canine HSP27 amino acid sequence includes three serine residues corresponding to sites in human HSP27 known to be phosphorylated by mitogen-activated protein kinase-activated protein (MAPKAP) kinase-2. To determine whether muscarinic receptors are coupled to a “stress response” pathway in smooth muscle culminating in phosphorylation of HSP27, we assayed MAPKAP kinase-2 activity and tyrosine phosphorylation of p38 mitogen-activated protein (MAP) kinase, the enzyme thought to activate MAPKAP kinase-2. Recombinant canine HSP27 expressed in Escherichia coli was a substrate for MAPKAP kinase-2 in vitro as well as a substrate for endogenous smooth muscle HSP27 kinase, which was activated by carbachol. Carbachol also increased tyrosine phosphorylation of p38 MAP kinase. SB-203580, an inhibitor of p38 MAP kinases, reduced activation of endogenous HSP27 kinase activity and blocked the shift in HSP27 charge isoforms to acidic forms. We suggest that HSP27 in airway smooth muscle, in addition to being a stress response protein, is phosphorylated by a receptor-initiated signaling cascade involving muscarinic receptors, tyrosine phosphorylation of p38 MAP kinase, and activation of MAPKAP kinase-2.

Muscarinic receptors in airways: recent developments

1990 ◽  
Vol 68 (5) ◽  
pp. 1777-1785 ◽  
Author(s):  
P. J. Barnes
Keyword(s):  
Smooth Muscle ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Ganglion Cells ◽  
Receptor Activation ◽  
Airway Control ◽  
Submucosal Glands ◽  
Recent Developments ◽  
And Function

Recently there have been important advances in our understanding of muscarinic receptors in airways that have important implications for understanding airway control and for future therapy of airway diseases. The transduction mechanisms involved in muscarinic receptor activation are now better understood. Receptor-linked phosphoinositide hydrolysis leads to release of calcium ions from intracellular stores, resulting in contraction of airway smooth muscle. At least five subtypes of muscarinic receptor have now been cloned, although only three subtypes can be distinguished pharmacologically. M1 receptors are facilitatory to neurotransmission in airway parasympathetic ganglion cells and have also been identified in airway submucosal glands and on the alveolar walls of human lung. M2 receptors are located on postganglionic nerves and function as powerful feedback inhibitory receptors (autoreceptors) that are likely to be involved in modulation of reflex bronchoconstriction. These receptors may be dysfunctional in asthmatic airways. M3 receptors are present on airway smooth muscle and submucosal glands and mediate the classical muscarinic effects in airways. Molecular biology techniques should now allow further study of the factors that regulate transcription and expression of muscarinic receptors in airways.

Effect of selective muscarinic antagonists on peristaltic contractions in opossum smooth muscle

1986 ◽  
Vol 250 (1) ◽  
pp. G50-G59 ◽  
Author(s):  
R. J. Gilbert ◽  
W. J. Dodds
Keyword(s):  
Smooth Muscle ◽  
Muscarinic Receptors ◽  
Vagal Stimulation ◽  
S Wave ◽  
S Waves ◽  
Circular Smooth Muscle ◽  
Primary Peristalsis ◽  
High Doses ◽  
Peristaltic Contractions ◽  
M2 Muscarinic Receptors

In this study we examined the role of M1- and M2-muscarinic receptors in the mediation of circular smooth muscle esophageal contractions elicited by pharmacological cholinergic stimulation and during peristalsis in anesthetized opossums. Esophageal-body contractions were induced by bethanechol administration, whereas peristalsis was elicited by pharyngeal stroking or cervical vagal stimulation. Contractions were measured by a low-compliance manometric recording system. The incidence and amplitude of bethanechol-induced contractions were antagonized by 4-diphenylacetoxy-n-methylpiperidine (4-DAMP) and atropine but not pirenzepine. 4-DAMP and atropine caused an increased velocity, decreased amplitude, and preferential reduction of the incidence of primary peristaltic contractions in the proximal smooth muscle esophagus. During long-train vagal stimulation, intra-stimulus A-waves had a velocity similar to primary peristalsis, whereas poststimulus B-waves showed a velocity considerably faster than primary peristalsis. Short-train vagal stimulation produced a contraction sequence, termed an "S-wave," that had a velocity similar to that of the A-wave. At low doses 4-DAMP increased the velocity and decreased the amplitude of A-wave and S-wave contractions, and at high doses 4-DAMP abolished both the A-wave and S-wave contractions. B-wave contractions were minimally affected by 4-DAMP. Pirenzepine had no effect on contractions induced by swallows or vagal stimulation. We conclude that M2-muscarinic receptors mediate esophageal contractions in the circular smooth muscle during primary peristalsis and during A-waves and S-waves induced by vagal stimulation, and M1-receptors do not have any important role in the excitatory neural pathway to the esophagus.(ABSTRACT TRUNCATED AT 250 WORDS)

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