Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchus.
BACKGROUND
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.
Benamou
A E M
AE
Centre for Equine Studies, Animal Health Trust, Lanwades Park, Kentford, Suffolk, UK.
Marlin
D J
DJ
Callingham
B C
BC
Hiley
R C
RC
Lekeux
R
R
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006736:Horses / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; C086539:BQ 788; D011189:Potassium Chloride; C072247:cyclo(Trp-Asp-Pro-Val-Leu)