Ipratropium bromide potentiates bronchoconstriction induced by vagal nerve stimulation in the guinea-pig

doi:10.1016/0014-2999(87)90251-2

European Journal of Pharmacology

Volume 139, Issue 2, 9 July 1987, Pages 187-191

https://doi.org/10.1016/0014-2999(87)90251-2 Get rights and content

Abstract

In anaesthetised guinea-pigs, brinchoconstriction induced by vagal nerve stimulation was potentiated by low doses of the antimuscarinic bronchodilator drug, ipratropium (0.01–1.0 μg/kg); the maximum effect was obtained with 1.0 μg/kg which doubled the bronchoconstriction. When the dose was increased above 1.0 μg/kg potentiation no longer occured; instead the vagally induced bronchoconstriction was antagonised. This was accompanied by reduction in the bronchoconstriction and bradycardia induced by i.v. acetylcholine, due to blockade of post-junctional muscarinic receptors in the airways and heart. With 10 μg/kg ipratropium responses elicited both by vagal stimulation and by exogenous acetylcholine were abolished. The results show that ipratropium is an antagonist for pre-junctional muscarinic inhibitory receptors on pulmonary parasymphathetic nerves and also confirm its potent antagonist actions on post-junctional muscarinic receptors in the airway smooth muscle. The effect of ipratropium in the lung depends, therefore, on the balance the pre- and post-junctional effects.

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Preclinical efficacy of THRX-200495, a dual pharmacology muscarinic receptor antagonist and β<inf>2</inf>-adrenoceptor agonist (MABA)
2012, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
In this guinea pig model of bronchoprotection, co-formulation of ipratropium and albuterol demonstrated potent, short-lasting bronchoprotection which was consistent with the frequency of administration (q.i.d.) in patients. These results were also consistent with the reported preclinical efficacy of ipratropium and albuterol [33–35]. Albuterol was 2.6-fold more potent than ipratropium when the MA and BA components of ipratropium/albuterol were pharmacologically isolated at 0.5 h post aerosol exposure.
Combinations of a muscarinic receptor antagonist (MA) and a β₂-adrenoceptor agonist (BA) improve bronchodilation in COPD patients to a greater extent than drugs with either mechanism alone. Here, using an in vivo model of bronchoprotection in guinea pigs, we characterize a single agent with dual-acting MA and BA activity, THRX-200495 (MABA). THRX-200495 was compared to a fixed-dose combination of a short-acting muscarinic receptor antagonist (SAMA) and a β₂-adrenoceptor agonist (SABA). The SAMA/SABA combination consisted of a 1:5.7 ratio of ipratropium and albuterol (the components of Combivent®). Conscious guinea pigs received aqueous nebulized solutions of vehicle or test compound by aerosol exposure. Bronchoprotective potency was estimated in anesthetized, tracheotomized and ventilated guinea pigs at predetermined time points after aerosol exposure by measuring changes in ventilation pressure. The individual (MA, BA) and composite (MABA) pharmacologies were assessed by determining protection against bronchoconstrictor responses induced by methacholine in the presence of propranolol (for MA activity), histamine (for BA activity) or methacholine (MABA activity). Bronchoprotection was calculated as percent inhibition of methacholine or histamine response relative to the vehicle group. THRX-200495 exhibited matched MA (ID₅₀ = 11.4 μg/mL) and BA (ID₅₀ = 11.2 μg/mL) potency and potent dual pharmacology (MABA ID₅₀ = 3.5 μg/mL) that persisted for over 24 h. The combination of ipratropium/albuterol exhibited bronchoprotective activity that was 2.6-fold more potent as a BA (ID₅₀ = 5.7 μg/mL) than as an MA (ID₅₀ = 14.6 μg/mL) at 0.5 h post-dose and 37-fold more potent as an MA (ID₅₀ = 4.3 μg/mL) than a BA (ID₅₀ = 159 μg/mL) at 1.5 h post aerosol exposure. Under MABA pharmacological conditions, ipratropium/albuterol produced potent bronchoprotective activity (ID₅₀ = 2.0/11.4 μg/mL) and an apparent additive effect of the two pharmacologies. In conclusion, a dual-acting prototypical MABA, THRX-200495, demonstrated potent, balanced and long-lasting bronchodilation in a guinea pig model of bronchoprotection that was greater than either the MA or BA mechanisms alone.
Application of the classical Einthoven model of bronchoconstriction to the study of inhaled bronchodilators in rodents
2011, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
A similar consistency was observed with tiotropium which is administered once a day in patients (Saberi and O'Donnell, 2005; Niewoehner et al., 2009) and maintained efficacy for 24 h in the Einthoven model. Thus, the duration of ipratropium and tiotropium in this model is consistent with both the clinical dosing regimens (Littner et al., 2000; Saberi and O'Donnell, 2005; Gelb et al., 2008; Niewoehner et al., 2009) and published preclinical studies (Fryer & Maclagan, 1987; Villetti et al., 2006; Casarosa et al., 2009; Gavaldá et al., 2009). In our study, salmeterol and indacaterol exhibited potent reversal of histamine-induced bronchoconstriction at 1.5 h, a time point at which the potency of albuterol was 65-fold lower than that of salmeterol.
The discovery of novel bronchodilators that treat human respiratory disorders has been guided by an array of animal models of bronchoconstriction which differ in technical complexity and experimental endpoints. Here, we apply methodology in which ventilation pressure provides a surrogate measure of airway tone (Einthoven, 1892) to assess the potency and duration of muscarinic antagonists and β₂-adrenergic agonists in two rodent species. The purpose of this study was to validate the Einthoven model of bronchoconstriction by testing two classes of bronchodilators that are approved for clinical use.
Conscious guinea pigs or rats, placed in an inhalation chamber, were dosed by nebulization with vehicle or test compound. Prior to testing, animals were anesthetized, tracheotomized and artificially ventilated. Changes in ventilation pressure were measured via a pressure transducer. Guinea pigs were challenged with doses of methacholine (1–32 μg/kg, i.v.) or histamine (1–64 μg/kg, i.v.) and rats were challenged with an infusion of methacholine (5–80 μg/kg, i.v.). Changes in ventilation pressure (cm H₂O) were calculated as peak post-challenge ventilation pressure − peak baseline ventilation pressure. The potency [ID₅₀, nebulizer concentration] and duration of bronchoprotective activity of ipratropium, tiotropium, albuterol, salmeterol and indacaterol were determined.
In guinea pig, ipratropium [ID₅₀ = 5.7 μg/mL] and tiotropium [ID₅₀ = 5.4 μg/mL] were equipotent, whereas albuterol [ID₅₀ = 117 μg/mL], was 65-fold and 23-fold less potent than salmeterol [ID₅₀ = 1.8 μg/mL] and indacaterol [ID₅₀ = 5.2 μg/mL], respectively. Only tiotropium and indacaterol exhibited 24 h bronchoprotection. In the rat, ipratropium [ID₅₀ = 4.4 μg/mL] and tiotropium [6.0 μg/mL] were equipotent. The bronchoprotective duration of tiotropium in the rat was ≥ 24 h.
The Einthoven model accurately determined the rank order of potency and duration of clinically used bronchodilators. The decreased experimental variability and reproducibility associated with the methodology of Einthoven model may offer significant advantages over other models of bronchoconstriction and thereby support the discovery of novel bronchodilators.
Selective muscarinic receptor antagonists for airway diseases
2001, Current Opinion in Pharmacology
Airway tone and airway hyperreactivity are mediated by the parasympathetic nerves that release acetylcholine onto muscarinic receptors (M₁–M₅). Stimulation of M₁ and M₃ muscarinic receptors causes bronchoconstriction. The M₁ muscarinic receptor is excitatory, and facilitates neuronal transmission at the parasympathetic ganglion. The M₂ receptor is an inhibitory prejunctional autoreceptor. The discovery of discrete muscarinic receptor subtypes prompted development of selective muscarinic receptor antagonists. Selective M₃ receptor antagonists and antagonists selective for M₁ and M₃ receptors have recently entered clinical trials and offer much promise for the treatment of airways diseases.
Anticholinergic therapy for airway diseases
2001, Life Sciences
Anticholinergics are commonly used in the treatment of airway diseases. While their effectiveness in chronic asthma offers no advantage over β-agonists, evidence continues to accumulate suggesting substantial additional benefit in acute asthma attacks. This increased response to anticholinergics suggest that cholinergic bronchoconstriction is increased in acute asthma. Multiple mechanisms related to changes in expression and function of inhibitory M2 muscarinic receptors on the airway parasympathetic nerves may be involved, and are discussed. The use of anticholinergics in chronic obstructive pulmonary disease and in rhinitis are also considered.
Eosinophil recruitment to the airway nerves
2001, Journal of Allergy and Clinical Immunology
Increased vagal reflexes contribute to bronchoconstriction in asthma. Antigen challenge of sensitized animals induces vagal hyperresponsiveness. This review will discuss the evidence that eosinophils increase release of acetylcholine from the parasympathetic nerves. After antigen challenge, eosinophils are actively recruited to the airway nerves, possibly through expression of chemotactic substances and adhesion molecules by the nerves. Tachykinins acting on neurokinin 1 receptors activate the eosinophils. Activated eosinophils release eosinophil major basic protein (MBP), which is an endogenous antagonist for M₂ muscarinic receptors. The M₂ muscarinic receptors on the parasympathetic nerves in the lungs normally inhibit release of acetylcholine. When M₂ receptors are blocked by MBP, acetylcholine release is increased, resulting in hyperresponsiveness. Neutralization of MBP with polyanionic substances restores M₂ receptor function and eliminates hyperresponsiveness. Antibodies to MBP prevent M₂ receptor dysfunction and hyperresponsiveness, as do antibodies to the adhesion molecule very late antigen 4, which prevent eosinophil migration. A low dose of dexamethasone, which does not affect total eosinophil influx into the lungs and airways, prevents eosinophils from clustering around the nerves and prevents antigen-induced M₂ dysfunction and hyperresponsiveness. Furthermore, animal studies show that viral infections, which are important precipitants of asthma attacks, and exposure to air pollutants such as ozone can also activate airway eosinophils, leading to a chain of events similar to that seen after antigen challenge. Finally, a similar clustering of eosinophils around airway nerves, as well as release of MBP onto the nerves, is seen in fatal asthma, suggesting that similar mechanisms may be involved in human airway hyperresponsiveness. (J Allergy Clin Immunol 2001;107:211-8.)
Status asthmaticus in children: A review
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Citation Excerpt :
Currently available anticholinergic agents are nonselective and antagonize both M3 and M2 receptors. M2-receptor antagonism may then cause bronchoconstriction, counteracting some of the M3-receptor–induced bronchodilatation.46 There is no direct adrenergic innervation to human airway smooth muscle.
About 10% of American children have asthma, and its prevalence, morbidity, and mortality have been increasing. Asthma is an inflammatory disease with edema, bronchial constriction, and mucous plugging. Status asthmaticus in children requires aggressive treatment with β-agonists, anticholinergics, and corticosteroids. Intubation and mechanical ventilation should be avoided if at all possible, as the underlying dynamic hyperinflation will worsen with positive-pressure ventilation. If mechanical ventilation becomes necessary, controlled hypoventilation with low tidal volume and long expiratory time may lessen the risk of barotrauma and hypotension. Unusual and nonestablished therapies for severe asthma are discussed.

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¹: Present address: University of California, San Fransisco, Cardiovascular Research Institute M-1327, Box 0130, San Fransisco, CA 94143, U.S.A.

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Ipratropium bromide potentiates bronchoconstriction induced by vagal nerve stimulation in the guinea-pig

Abstract

European, J. Pharmacol.

Binding of various anticholinergics to the muscarinic receptors from various tissues

Postgrad, Med. J.

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

Br. J. Pharmacol.

The effects on salivation and heart rate following intravenous injection of Sch 1000 and Sch 1000 MDI in healthy volunteers

Postgrad. Med. J.

Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity

Br. Med. J.

Contributions to the physiology of the lungs. Part 1, the bronchial muscles and their innervation and the action of drugs upon them

J. Physiol.