Refractoriness of eucapnic hyperventilation-induced bronchoconstriction in rabbits

Area of Science:

• Respiratory Physiology
• Pharmacology

Background:

• Repeated airway challenges can induce refractoriness, a phenomenon where subsequent exposures elicit a diminished response.
• Understanding the mechanisms behind airway refractoriness is crucial for managing respiratory conditions.

Purpose of the Study:

• To investigate the mechanisms underlying refractoriness in bronchoconstriction following repeated hyperventilation in sensitized rabbits.
• To determine the role of H2-receptors and bronchodilating prostanoids in this refractory response.

Main Methods:

• 18 sensitized rabbits were divided into control, cimetidine-treated, and indomethacin-treated groups.
• Hyperventilation with dry air (5% CO2) was administered twice, with measurements of total lung resistance (RL) and dynamic compliance (Cdyn) before and after each challenge.
• Refractoriness was assessed by comparing the bronchoconstrictive response after the first and second hyperventilation challenges.

Main Results:

• Control rabbits exhibited significant refractoriness to bronchoconstriction after the second hyperventilation challenge (max %RL reduced from 49% to 16%).
• Cimetidine (H2-receptor antagonist) and indomethacin (prostaglandin inhibitor) treatments abolished this refractoriness, with no significant reduction in bronchoconstriction after the second challenge.
• Maximal increases in percent RL were 42% and 60% after the first challenge in cimetidine and indomethacin groups, respectively, and remained high (35% and 60%) after the second challenge.

Conclusions:

• H2-receptors and bronchodilating prostanoids are key mediators in the development of refractoriness to bronchoconstriction after repeated hyperventilation in sensitized rabbits.
• Pharmacological blockade of H2-receptors or prostanoid synthesis prevents the development of this airway refractoriness.