Application of the classical Einthoven model of bronchoconstriction to the study of inhaled bronchodilators in rodents.
BACKGROUND
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 β(2)-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.


METHODS
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 (cmH(2)O) were calculated as peak post-challenge ventilation pressure-peak baseline ventilation pressure. The potency [ID(50), nebulizer concentration] and duration of bronchoprotective activity of ipratropium, tiotropium, albuterol, salmeterol and indacaterol were determined.


RESULTS
In guinea pig, ipratropium [ID(50)=5.7 μg/mL] and tiotropium [ID(50)=5.4 μg/mL] were equipotent, whereas albuterol [ID(50)=117 μg/mL], was 65-fold and 23-fold less potent than salmeterol [ID(50)=1.8 μg/mL] and indacaterol [ID(50)=5.2 μg/mL], respectively. Only tiotropium and indacaterol exhibited 24h bronchoprotection. In the rat, ipratropium [ID(50)=4.4 μg/mL] and tiotropium [6.0 μg/mL] were equipotent. The bronchoprotective duration of tiotropium in the rat was ≥ 24 h.


CONCLUSIONS
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.
McNamara
Alexander
A
Theravance, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, USA. amcnamara@theravance.com
Pulido-Rios
Maria Teresa
MT
Hegde
Sharath S
SS
Martin
William J
WJ
D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D012123:Pulmonary Ventilation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists