From the Guidelines
Endothelin primarily causes bronchoconstriction in the airways. The mechanism of action involves endothelin-1, the most potent isoform of the endothelin family, acting on specific receptors (primarily ETA and ETB receptors) in bronchial smooth muscle to induce contraction, leading to narrowing of the airways. This bronchoconstricting effect is particularly significant in asthma and other respiratory conditions where endothelin levels are often elevated, as noted in studies on exercise-induced bronchoconstriction 1. The pathophysiology of such conditions involves the creation of a hyperosmolar environment, leading to mast cell degranulation and the release of mediators that can cause bronchoconstriction and inflammation of the airway. Although endothelin can have complex actions in the respiratory system, including some bronchodilatory effects in certain circumstances through nitric oxide release from epithelial cells, the net physiological effect of endothelin in the airways is bronchoconstriction, contributing to airway hyperresponsiveness in respiratory diseases. Key factors influencing the severity of bronchoconstriction include the water content of the inspired air and the level of ventilation achieved and maintained during exercise, as discussed in the context of exercise-induced bronchoconstriction updates 1.
Mechanism of Action
- Endothelin-1 acts on ETA and ETB receptors in bronchial smooth muscle.
- This action leads to calcium mobilization within smooth muscle cells, triggering contraction.
- The contraction results in the narrowing of the airways, contributing to bronchoconstriction.
Clinical Implications
- Bronchoconstriction is a significant effect of endothelin in the airways, particularly in conditions like asthma.
- Management of conditions like exercise-induced bronchoconstriction may involve therapeutic interventions to prevent or alleviate bronchoconstriction, such as short-acting b2-agonists (SABAs) for bronchodilation and anti-inflammatory medications for inflammation control, as discussed in the guidelines for exercise-induced bronchoconstriction management 1.
- Understanding the pathophysiology and the role of endothelin in bronchoconstriction can inform the development of targeted therapies to improve outcomes in respiratory diseases.
From the Research
Endothelin's Effect on Airway Tone
- Endothelin-1 (ET-1) has been shown to induce bronchoconstriction in asthma patients, with a potency around 100 times that of methacholine 2.
- The study found that all asthmatic subjects displayed rapid-onset, dose-dependent bronchoconstriction to ET-1, with no significant bronchoconstriction observed in healthy volunteers 2.
- Another study found that ET-1 levels were elevated during exacerbations of asthma and chronic obstructive pulmonary disease (COPD), and that hypoxemia stimulates ET-1 secretion 3.
Mechanisms of Endothelin-1
- Endothelin-1 has been implicated in the pathogenesis of asthma and COPD, with pro-inflammatory properties and involvement in airway structural remodeling 4.
- The interaction of ET-1 with other cytokines is thought to play a role in the development of bronchial hyperresponsiveness, a fundamental characteristic of asthma 4.
- ET-1 levels have been found to be higher in COPD patients who experience nocturnal oxyhemoglobin desaturation, and correlate negatively with the degree of desaturation 3.
Comparison to Other Bronchodilators
- The primary study on bronchodilators does not mention endothelin-1 as a bronchodilator, instead focusing on β(2)-adrenoceptor agonists, muscarinic receptor antagonists, and xanthines as the main classes of bronchodilators 5.
- There is no evidence to suggest that endothelin-1 has a bronchodilatory effect, with all studies indicating its role as a bronchoconstrictor 2, 4, 3.