Neuronal muscarinic receptors attenuate vagally‐induced contraction of feline bronchial smooth muscle

Blaber, L. C.; Fryer, A.D.; Maclagan, Jennifer

doi:10.1111/j.1476-5381.1985.tb08951.x

Cited by 122 publications

(61 citation statements)

References 28 publications

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“…Release of ACh from parasympathetic nerves is normally locally controlled by inhibitory neuronal M 2 muscarinic receptors (16)(17)(18)(19)(20), which were initially described on nerves supplying lungs in guinea pigs (19) and have subsequently been described in the parasympathetic nerves supplying the lungs of all species studied thus far (22,(33)(34)(35)(36)(37)(38), including humans. Loss of M 2 receptor function has been described in asthma (21,23) and is a common feature of many different animal models of airway hyperresponsiveness, including acute infection with parainfluenza virus (24), sensitization and challenge with antigen (26,33), acute exposure to ozone (25), and acute exposure to organophosphate pesticides (39).…”

Section: Discussionmentioning

confidence: 99%

“…In the lungs, M 2 muscarinic receptors limit acetylcholine (ACh) release from parasympathetic nerves (16)(17)(18), thereby limiting vagally induced bronchoconstriction (19,20). Dysfunctional M 2 muscarinic receptors on airway parasympathetic nerves result in airway hyperresponsiveness in humans with asthma (21)(22)(23) and in animal models of asthma (24)(25)(26).…”

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Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Nie

Jacoby

Fryer

2014

Am J Respir Cell Mol Biol

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Obesity is a substantial risk factor for developing asthma, but the molecular mechanisms underlying this relationship are unclear. We tested the role of insulin in airway responsiveness to nerve stimulation using rats genetically prone or resistant to diet-induced obesity. Airway response to vagus nerve stimulation and airway M 2 and M 3 muscarinic receptor function were measured in obeseprone and -resistant rats with high or low circulating insulin. The effects of insulin on nerve-mediated human airway smooth muscle contraction and human M 2 muscarinic receptor function were tested in vitro. Our data show that increased vagally mediated bronchoconstriction in obesity is associated with hyperinsulinemia and loss of inhibitory M 2 muscarinic receptor function on parasympathetic nerves. Obesity did not induce airway inflammation or increase airway wall thickness. Smooth muscle contraction to acetylcholine was not increased, indicating that hyperresponsiveness is mediated at the level of airway nerves. Reducing serum insulin with streptozotocin protected neuronal M 2 receptor function and prevented airway hyperresponsiveness to vagus nerve stimulation in obese rats. Replacing insulin restored dysfunction of neuronal M 2 receptors and airway hyperresponsiveness to vagus nerve stimulation in streptozotocintreated obese rats. Treatment with insulin caused loss of M 2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation in obese-resistant rats, and inhibited human neuronal M 2 receptor function in vitro. This study shows that it is not obesity per se but hyperinsulinemia accompanying obesity that potentiates vagally induced bronchoconstriction by inhibiting neuronal M 2 muscarinic receptors and increasing acetylcholine release from airway parasympathetic nerves.Keywords: hyperinsulinemia; obesity; asthma; airway responsiveness; neural M 2 muscarinic receptor Clinical RelevanceObesity-induced asthma does not respond well to traditional anti-inflammatory therapies, suggesting that it is a unique asthma phenotype. Here we show that hyperinsulinemia causes airway hyperresponsiveness to vagus nerve stimulation in obese rats. In human trachea and in rats, we demonstrate that insulin inhibits M 2 muscarinic receptors on airway parasympathetic nerves, resulting in increased acetylcholine release and increased airway contraction. Because hyperinsulinemia is greater and more prevalent in obese individuals, these data may explain why obese individuals are prone to asthma exacerbations and suggest that anticholinergic drugs may be effective in this specific phenotype of asthma.In the United States, 31% of adults and 15% of children are obese. In obese and overweight individuals, the prevalence of asthma (1-3) and the rate of new-onset asthma have increased (4-6). Obese patients with asthma also have increased severity of illness and reduced effectiveness of steroids compared with nonobese patients with asthma (1, 6, 7). The mechanisms by which obesity predisposes to asthma are unclear, limi...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Nie

Jacoby

Fryer

2014

Am J Respir Cell Mol Biol

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“…Bronchoconstrictions were measured as increases in peak inspiratory pressure during electrical stimulation. Lung compliance was not independently measured; however, the contribution of lung compliance to rapid changes in airway pressure using this technique are presumed negligible based on prior work (23). R837 (0.003-3 mg/kg, intravenous) was given after every four electrical stimulations.…”

Section: In Vivo Guinea Pig Physiologymentioning

confidence: 99%

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.Keywords: Toll-like receptor 7; imiquimod; nitric oxide; asthma; nerve Toll-like receptor (TLR) 7 is a pattern recognition receptor in the lungs (1-3) that detects single-stranded RNA genomes, common to many respiratory viruses (4). Respiratory viruses cause airway hyperreactivity (an abnormal tendency to contract) (5, 6) and asthma exacerbations (7). A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10). Furthermore, in mouse models of allergic airway inflammation, the TLR7 imidazoquinoline agonists imiquimod (R837) and resiquimod (R848) reduced airway hyperreactivity, airway eosinophilia, goblet cell hyperplasia, and smooth muscle hypertrophy (11-14), whereas TLR7 knockout mice were prone to the development of asthma-like airway pathology after pneumovirus infection (15). These studies suggest that TLR7 may be protective against the development of allergic type 2 T-helper cell airway inflammation, possibly by altering the Th1 versus Th2 immune balance (16). Similarly, a TLR7 agonist is currently i...

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“…This hypothesis is mainly based on indirect evidence: gallamine, which is known to antagonize ACh at muscarinic receptors of the heart, potentiates bronchoconstriction induced by electrical stimulation of the vagus nerve, while the cholinoceptor agonist pilocarpine inhibits this response (Fryer & Maclagan, 1984;Blaber et al, 1985). These authors suggest that gallamine and pilocarpine are a selective antagonist and agonist, respectively, of prejunctional muscarinic receptors in the airways.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies suggest the existence of prejunctional muscarinic receptors located on airway parasympathetic nerve terminals of guinea-pigs (Fryer & Maclagan, 1984), cats (Blaber et al, 1985) and man (Minette et al, 1987) and endowed with an inhibitory function on ACh release. This hypothesis is mainly based on indirect evidence: gallamine, which is known to antagonize ACh at muscarinic receptors of the heart, potentiates bronchoconstriction induced by electrical stimulation of the vagus nerve, while the cholinoceptor agonist pilocarpine inhibits this response (Fryer & Maclagan, 1984;Blaber et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the potentiation of neurally‐induced bronchoconstriction by gallamine in the guinea‐pig

Monte¹,

Omini

Subissi³

1990

British J Pharmacology

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1 Electrical stimulation of the cervical vagi (15 Hz, 0.2 ms, 3s, 7-15 V) produced a slight bronchoconstriction in the anaesthetized guinea-pig. This effect was fully abolished by atropine, while gallamine (0.1-lOymol kg-1) produced a dose-dependent increase up to ten fold.2 Gallamine-induced potentiation of neurally-mediated bronchoconstriction was not inhibited by depletion of sensory neuropeptides with capsaicin or by pretreatment with pyrilamine. In propranololpretreated guinea-pigs the potentiation induced by gallamine 3 and 10 imol kg1 was inhibited by 40 and 46%, respectively. 3 Physostigmine (0.5 mg kg-1) produced a very slight and slowly developing bronchoconstriction in the anaesthetized guinea-pig, which was also potentiated dose-dependently by gallamine (0.1-10umol kg-1). 4 Gallamine (1 0 mol kg 1) potentiated the bronchial anaphylactic response induced by aerosol challenge with ovalbumin in actively sensitized guinea-pigs. 5 These results suggest that neither sensory neuropeptides nor histamine are involved in the gallamineinduced potentiation of neurally-mediated bronchoconstriction, while inhibition of the sympathetic nervous system may play a minor role. They are in general agreement with the hypothesis that gallamine antagonizes acetylcholine selectively at prejunctional muscarinic receptors in the guinea-pig airways, thus increasing its release from parasympathetic nerve terminals. These autoreceptors appear to be operant during anaphylactic bronchoconstriction.

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Neuronal muscarinic receptors attenuate vagally‐induced contraction of feline bronchial smooth muscle

Cited by 122 publications

References 28 publications

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Mechanism of the potentiation of neurally‐induced bronchoconstriction by gallamine in the guinea‐pig

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