Endothelins constrict guinea pig tracheas by multiple mechanisms

Area of Science:

• Pharmacology
• Respiratory Physiology

Background:

• Endothelins (ETs) are vasoactive peptides with known roles in cardiovascular function.
• Their specific role in airway smooth muscle contraction, particularly in guinea pigs, requires further elucidation.

Purpose of the Study:

• To investigate the mechanism of endothelin-induced tracheal smooth muscle contraction in guinea pigs.
• To determine the relative potencies of different endothelin isoforms (ET-1, ET-2, ET-3) on tracheal rings.
• To explore the involvement of calcium influx and inflammatory mediators in ET-1-mediated constriction.

Main Methods:

• Isometric measurement of tracheal ring constriction in response to various endothelins.
• Assessment of calcium channel blockers (nicardipine, diltiazem) and mediator inhibitors (FPL55712, indomethacin, OKY046, diphenhydramine).
• Immunoassay of ET-1 in airway tissue and evaluation of mast cell degranulation using compound 48/80.

Main Results:

• Endothelins induced a dose-dependent tracheal constriction, with ET-1 = ET-2 > ET-3 potency.
• Epithelium removal shifted dose-response curves leftward, indicating epithelium-derived factors may modulate responses.
• Constriction required extracellular calcium, primarily entering through non-voltage-dependent channels.
• Inhibitors of lipid mediators and histamine release, along with mast cell degranulation, suppressed the contractile response.

Conclusions:

• Endothelin-1 (ET-1) induces tracheal contraction in guinea pigs through both direct smooth muscle effects and indirect mechanisms.
• Indirect effects involve the release of lipid mediators and histamine from inflammatory cells, particularly mast cells.
• These findings highlight the complex interplay between endothelins and inflammatory pathways in regulating airway smooth muscle tone.