Endothelin-1 receptor density, distribution, and function in human isolated asthmatic airways

Area of Science:

• Pulmonary Medicine
• Pharmacology
• Molecular Biology

Background:

• Endothelin-1 (ET-1) is a potent peptide that causes bronchoconstriction and mitogenesis in airway smooth muscle.
• These actions of ET-1 may significantly contribute to bronchial obstruction in asthma.
• The status of receptor-effector systems mediating ET-1 actions in asthmatic airways is unknown.

Purpose of the Study:

• To evaluate the density, distribution, and function of ET-1 receptors in asthmatic and nonasthmatic airways.
• To determine the specific receptor subtypes involved in ET-1-mediated actions.
• To investigate potential desensitization of these receptors in asthma.

Main Methods:

• Quantitative autoradiography to assess receptor binding sites for [125I]-ET-1.
• Isometric-tension recording to measure airway smooth muscle contraction.
• Pharmacological characterization using receptor subtype-selective antagonists (e.g., BQ-123).

Main Results:

• Similar numbers of specific [125I]-ET-1 binding sites were found in asthmatic and nonasthmatic airways, primarily in airway smooth muscle.
• The ETB-receptor subtype was the predominant receptor (82% in asthmatic, 88% in nonasthmatic), mediating contraction.
• Asthmatic bronchial smooth muscle showed significantly reduced sensitivity to ETB receptor activation, suggesting desensitization.

Conclusions:

• ET-1 receptor density is similar in asthmatic and nonasthmatic airways, with ETB receptors being dominant.
• Asthmatic airways exhibit desensitization of ETB receptors, leading to reduced contractile responses to ET-1.
• A non-ETB, BQ-123-resistant mechanism and ETA sites involved in prostanoid release/proliferation may also play roles.