Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchus.
Abstract: There is currently little published information about the effects of endothelin-1 (ET-1), a potent endogenous spasmogen of vascular and airway smooth muscle, on pulmonary vasculature and airways or which ET receptor subtypes mediate ET-1-induced vasoconstrictive and bronchoconstrictive action in the horse. Objective: To investigate the effect of endothelin-1 (ET-1) on smooth muscle from isolated equine pulmonary artery and bronchus. In addition, the roles of ETA and ETB receptors in ET-1 mediated contraction in these tissues were assessed. Methods: The force generation of ring segments from pulmonary arteries or third-generation airways (obtained from horses subjected to euthanasia for orthopaedic reasons) were studied in an organ bath at 37 degrees C in response to exogenous endothelin and selective endothelin A (BQ123) or B receptor (BQ788) antagonists. Results: ET-1 produced concentration-dependent contractions of the equine pulmonary artery and bronchus. The threshold for contraction was 10(-10) and 10(-9) mol/l ET-1 for pulmonary artery and bronchus, respectively. The maximal contraction induced by the highest ET-1 concentration (10(-7) mol/l) was 173 and 194% of the contraction obtained with 100 mmol/l KCl in pulmonary artery and bronchus, respectively. ET-1 potency was 25 times greater in equine pulmonary artery than in equine bronchus (concentration of ET-1 producing 50% of maximal contraction [EC50] = 5.6 10(-9) mol/l and 2.2 10(-8) mol/l, respectively). In pulmonary artery, ET-1 induced contractions were significantly inhibited by the ETA receptor antagonist BQ123 (1 micromol/l; dose-response curve to ET-1 was shifted to the right by 5.4-fold), but not by the ETB antagonist BQ788. In bronchus, dose-responses curves to ET-1 were shifted to the right by BQ123 (1 micromol/l; 2.5-fold), but not by BQ788 (1 micromol/l). In the presence of both antagonists, the dose-response curve to ET-1 was shifted to the right by 4.5-fold. Conclusions: These functional studies demonstrate that ET-1 is a potent spasmogen of equine third generation pulmonary artery and bronchus, and that contractions are mediated via ETA receptors in the former and both ETA and ETB receptors in the latter. Conclusions: Endothelin receptor antagonists may have potential for treating equine pulmonary hypertension or bronchoconstriction.
Publication Date: 2003-03-18 PubMed ID: 12638797DOI: 10.2746/042516403776114243Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research investigates the effects of endothelin-1 (ET-1), a naturally occurring substance that causes muscle spasms, on the pulmonary arteries and airways of horses. It further explores which ET receptor types are responsible for ET-1-induced blood vessel and airway constriction. Results indicate that ET-1 is a strong stimulant of the horse’s pulmonary artery and bronchus, and its reactions are governed by ETA receptors.
About Endothelin-1 (ET-1) and the Experiment
- Endothelin-1 (ET-1) is an endogenous (naturally occurring within the body) spasmogen, meaning it triggers contractions in smooth muscle tissues, with effects on both vascular and airway smooth muscle – the kinds found in blood vessels and airways.
- In this study, the scientists wanted to observe the effects of ET-1 on the pulmonary artery and bronchus of horses, with the aim of understanding exactly how ET-1 creates vasoconstriction (narrowing of blood vessels) and bronchoconstriction (narrowing of airways).
The Experiment and Methods Used
- The scientists extracted ring segments from the pulmonary arteries and third-generation airways of horses that had been euthanized for orthopedic reasons.
- These isolated tissues were then subjected to different concentrations of ET-1 and then separately to selective ET A or B receptor antagonists, BQ123 and BQ788, to see how they would respond.
- The purpose of BQ123 and BQ788 was to block the activity of ETA and ETB receptors, respectively.
Results of the Experiment
- ET-1 produced concentration-based contractions of the isolated equine pulmonary artery and bronchus. However, the potency of ET-1 was found to be 25 times greater in the pulmonary artery than in the bronchus.
- In pulmonary arteries, contractions created by ET-1 were significantly reduced when treated with BQ123, the ETA receptor antagonist, but not with BQ788, the ETB receptor antagonist. This suggested that ET-1’s actions in the pulmonary arteries are mediated predominantly by ETA receptors.
- In bronchus, both BQ123 and BQ788 shifted the dose-response curves to ET-1 to the right. This meant both ETA and ETB receptors were involved in mediating the effects of ET-1 in the bronchus.
Potential Applications of the Study
- The findings of this study have direct implications for the treatment of equine pulmonary hypertension (high blood pressure in the arteries that transport blood to the lungs) or bronchoconstriction. Inhibitors targeted at ET receptors, such as BQ123, could be used to reduce the spasmodic effects of ET-1, potentially opening up new therapeutic angles.
Cite This Article
APA
Benamou AE, Marlin DJ, Callingham BC, Hiley RC, Lekeux R.
(2003).
Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchus.
Equine Vet J, 35(2), 190-196.
https://doi.org/10.2746/042516403776114243 Publication
Researcher Affiliations
- Centre for Equine Studies, Animal Health Trust, Lanwades Park, Kentford, Suffolk, UK.
MeSH Terms
- Animals
- Antihypertensive Agents / pharmacology
- Bronchi / drug effects
- Bronchi / physiology
- Bronchoconstriction / drug effects
- Dose-Response Relationship, Drug
- Endothelin Receptor Antagonists
- Endothelin-1 / pharmacology
- Female
- Horses / physiology
- In Vitro Techniques
- Male
- Muscle, Smooth, Vascular / drug effects
- Oligopeptides / pharmacology
- Peptides, Cyclic / pharmacology
- Piperidines / pharmacology
- Potassium Chloride / pharmacology
- Pulmonary Artery / drug effects
- Pulmonary Artery / physiology
- Receptor, Endothelin A
- Receptor, Endothelin B
- Receptors, Endothelin / physiology
- Vasoconstrictor Agents / pharmacology
Citations
This article has been cited 3 times.- Sylvester JT, Shimoda LA, Aaronson PI, Ward JP. Hypoxic pulmonary vasoconstriction. Physiol Rev 2012 Jan;92(1):367-520.
- Polikepahad S, Haque M, Francis J, Moore RM, Venugopal CS. Characterization of endothelin receptors in the peripheral lung tissues of horses unaffected and affected with recurrent airway obstruction. Can J Vet Res 2008 Jul;72(4):340-9.
- Venugopal CS, Polikepahad S, Holmes EP, Heuvel JV, Leas TL, Moore RM. Endothelin receptor alterations in equine airway hyperreactivity. Can J Vet Res 2006 Jan;70(1):50-7.
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