Spasmogenic action of endothelin‐1 on isolated equine pulmonary artery and bronchus

Abstract

Summary Reasons for performing study: 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. Objectives: 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 fororthopaedic reasons) were studied in an organ bath at 37°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 μmol/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 μmol/l; 2.5‐fold), but not by BQ788 (1 μmol/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. Potential clinical relevance: Endothelin receptor antagonists may have potential for treating equine pulmonary hypertension or bronchoconstriction.

Physiologic responses and plasma endothelin-1 concentrations associated with abrupt cessation of nitric oxide inhalation in isoflurane-anesthetized horses

“…Increased MPAP and decreased Pao 2 were also associated with increased plasma ET-1 concentrations in endotoxemic pigs. 13 Endothelin-1 is also a potent vasoconstrictor in the pulmonary vessels in horses 24,25 and could potentially contribute to hypoxia in anesthetized horses. However, plasma ET-1 concentrations did not change at any time during the study of this report, which could explain the lack of a rebound effect.…”

Oxygenation and plasma endothelin‐1 concentrations in healthy horses recovering from isoflurane anaesthesia administered with or without pulse‐delivered inhaled nitric oxide

“…The C group of horses, which were more hypoxaemic than the NO group at all time points also had higher ET‐1 concentrations at all time points, although the variability of the measurements was high and significance was only reached at Times 2, 20 and 25. Endothelin‐1 is also a potent vasoconstrictor in the pulmonary vessels in horses (Benamou et al. 2001, 2003) and ET‐1 increases in horses known to have recurrent airway obstruction (Benamou et al.…”

Thermographic study of in vivo modulation of vascular responses to phenylephrine and endothelin-1 by dexamethasone in the horse

“…It is possible that differences between species or technique could account for our inability to detect antagonism by these drugs. Indeed, up to now, blocking of ET B -receptors in the different vascular beds of the horse has been unsuccessful (Benamou et al 2003;Katz et al 2003). It has also been reported that the blockade of ET B -receptors in other species does not always result in an alteration of vasomotor tone (Pang et al 1998;Lipa et al 1999;Leslie et al 2004).…”

“…All solutions were equilibrated to room temperature (22°C) prior to injection. The concentrations of ET-1, antagonists and PHE were based on in vitro and in vivo vascular dose-response studies (Elliott et al 1994;Lawrence and Brain 1994;Pang et al 1998;Lipa et al 1999;Katugampola et al 2000;Venugopal et al 2001;Benamou et al 2003;Katz et al 2003;Bowen et al 2004;Wilson et al 2004).…”