Endothelin in the equine hypoxic pulmonary vasoconstrictive response to acute hypoxia.
Elevated concentrations of endothelin (ET), a potent endothelium-derived vasoactive peptide, have been reported in a number of pathophysiological conditions associated with pulmonary hypertension, both in the horse and other species. We have previously shown, both in vitro and in vivo, that the pulmonary and systemic vascular response to exogenous ET is mediated predominantly via ET(A) receptors. Our hypothesis in the present study was that ET is involved in the equine hypoxic pulmonary vasoconstrictive response to acute hypoxia. In this study, we investigated the effects of a selective ET(A) receptor antagonist on hypoxic pulmonary hypertension in the mature horse. Horses were exposed to a 10 min period of hypoxia (F(I)O2 approximately 0.11) on 2 occasions, with and without pretreatment with the selective ET(A) receptor antagonist TBC11251 (10 mg/kg bwt i.v.). Hypoxia increased mean pulmonary artery pressure (PAP) from 18.3+/-0.9 (mean +/- s.e. normoxia) to 28.0+/-0.8 mmHg (hypoxia) in the session without ET(A) receptor antagonism. Carotid arterial pressure (CAP) also increased progressively throughout the period of hypoxic challenge and at the end was 153+/-5 mmHg (hypoxia) compared to during normoxia (140+/-5 mmHg). There was no significant overall effect of ET(A) receptor antagonism on the haemodynamic or ventilatory responses to acute hypoxia. However, between 5 and 10 min of hypoxia there was a trend for the mean PAP to diverge in the 2 treatments, which just failed to reach significance at 10 min of hypoxia (P = 0.053). In conclusion, this study describes the haemodynamic and ventilatory changes in response to a period of acute hypoxia in the adult horse. The results do not support a role for ET as a mediator of acute HPV in the horse, but suggest that it may be involved as a modulator or in the slower (>10 min) phase of HPV.
Benamou
A E
AE
Centre for Equine Studies, Animal Health Trust, Kentford, Newmarket, UK.
Marlin
D J
DJ
Lekeux
P
P
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects*; D006734:Horse Diseases / Q000517:prevention & control*; D006736:Horses; D000860:Hypoxia / Q000517:prevention & control / Q000662:veterinary*; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011897:Random Allocation; D044022:Receptor, Endothelin A; D012119:Respiration / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014662:Vasoconstrictor Agents / Q000494:pharmacology* / Q000627:therapeutic use
D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D044022:Receptor, Endothelin A; D013876:Thiophenes; D014662:Vasoconstrictor Agents; C106276:sitaxsentan