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. 2006 Jan;70(1):50-7.

Endothelin receptor alterations in equine airway hyperreactivity

Changaram S Venugopal  1 , Sumanth Polikepahad, Earnestine P Holmes, John Vanden Heuvel, Tara L Leas, Rustin M Moore
Affiliations

Endothelin receptor alterations in equine airway hyperreactivity

Changaram S Venugopal et al. Can J Vet Res. 2006 Jan.

Abstract
in English, French

The purpose of this study was to evaluate the role of endothelin-1 (ET-1) and its receptors in the airway hyperreactivity of horses with obstructive pulmonary disease associated with summer pasture (SPAOPD). The right diaphragmatic lobe of the lung of 8 clinically healthy (unaffected) and 8 SPAOPD-affected horses was collected immediately after euthanasia. Bronchial rings (4 mm wide) were prepared and mounted in organ baths and attached to force transducers interfaced with a polygraph. Four rings were used to study each ET-1 receptor; 1 ring served as the control, and the other 3 were incubated with 10(-9), 10(-7), or 10(-5) M of either BQ-123, an ET(A)-receptor antagonist, or IRL-1038, an ET(B)-receptor antagonist. Cumulative concentrations (10(-8.5) to 10(-6) M) of ET-1 were applied to all rings. Using pooled pulmonary tissue from different regions of the lung, we performed a reverse-transcription polymerase chain reaction (RT-PCR) to determine ET(B)-receptor gene expression. Although ET-1 caused concentration-dependent bronchial ring contraction in both groups of horses, the rings of SPAOPD-affected horses had significantly greater contraction than the rings of unaffected horses. Whereas ET(A)-receptor blockade significantly increased the response to ET-1 in unaffected horses, ET(B)-receptor blockade significantly decreased the response in affected horses. The pA2 values showed a nonsignificant decrease in ET(A)-receptor affinity and a significant increase in ET(B)-receptor affinity in affected horses compared with unaffected horses. The ET(B)-receptor mRNA expression of the pooled pulmonary tissue showed a nonsignificant increase in affected horses compared with unaffected horses. The airway hyperreactivity to ET-1 observed in the bronchial rings from the affected horses appears to be due in part to activation of pulmonary ET(B) receptors, which appear to be inactive in unaffected horses.

Afin d’évaluer le rôle de l’endotheline-1 (ET-1) et de ses récepteurs dans l’hyper-réactivité des voies respiratoires de chevaux avec une maladie pulmonaire obstructive associée au pâturage d’été (SPAOPD), le lobe diaphragmatique droit du poumon de 8 chevaux cliniquement sains (non-affectés) et 8 chevaux souffrant de SPAOPD a été prélevé immédiatement après l’euthanasie. Des anneaux bronchiques (4 mm de largeur) ont été préparés et montés dans des bains d’organe et attachés à des transducteurs de force interfacés à un polygraphe. Quatre anneaux ont été utilisés pour étudier chaque récepteur de l’endotheline; 1 anneau servait de témoin, et les 3 autres anneaux ont été incubés avec 10−9, 10−7 ou 10−5 M de BQ123, un antagoniste de récepteur ETA, ou IRL1038, un antagoniste de récepteur ETB. Des concentrations cumulatives (10−8,5 à 10−6 M) de ET-1 ont été appliquées à tous les anneaux. En utilisant un pool de tissu pulmonaire provenant de différentes régions du poumon, une épreuve d’amplification en chaîne par la polymérase utilisant la transcriptase reverse (RT-PCR) a été effectuée pour déterminer l’expression du gène du récepteur ETB. Bien que ET-1 ait entraîné une contraction dose-dépendante des anneaux bronchiques dans les deux groupes de chevaux, les anneaux de chevaux souffrant de SPAOPD montraient une contraction significativement plus marquée que les anneaux des chevaux sains. Alors que le bloc des récepteurs ETA augmenta significativement la réponse à ET-1 chez les chevaux normaux, le bloc de ETB diminua significativement la réponse chez les chevaux malades. Les valeurs de pA2 ont montré une réduction non-significative de l’affinité pour le récepteur ETA et une augmentation significative pour le récepteur ETB chez les chevaux malades comparativement aux chevaux sains. L’expression de l’ARNm de ETB dans le pool de tissu pulmonaire a montré une augmentation non-significative chez les chevaux malades comparativement aux animaux sains. L’hyper-réactivité des voies respiratoires envers ET-1 observée dans les anneaux bronchiques des chevaux malades semble être causée en partie à l’activation des récepteurs pulmonaires ETB, récepteurs qui semblent inactifs chez les chevaux cliniquement normaux.

(Traduit par Docteur Serge Messier)

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Figures

Figure 1
Figure 1
Mean concentration–response relationship, ± the standard error of the mean (sχ̄), of bronchial rings from 8 horses affected by obstructive pulmonary disease associated with summer pasture (SPAOPD) (black triangles) and 8 unaffected horses (white squares), the rings having been bathed with graded concentrations of endothelin-1 (ET-1), as a percentage response to carbachol 10−3 M, which represents the maximum contractile response of the tissue. Statistical significance (*P < 0.01, **P < 0.001) was evident at 10−7 M, 10−6.5 M, and 10−6 M concentrations of ET-1.
Figure 2
Figure 2
Mean ± standard error of the mean (sχ̄) concentration–response relationships of similarly bathed bronchial rings from the 8 unaffected horses in the absence of endothelin (ET)-receptor antagonists (black triangles; control rings), in the presence of 10−5 M of the ETA–receptor antagonist BQ-123 (white circles), and in the presence of 10−5 M of the ETB antagonist IRL-1038 (white squares). The presence of the ETA-receptor antagonist significantly (*P = 0.006) increased the overall contractile response of the rings to ET-1 compared with that for the control rings.
Figure 3
Figure 3
Mean ± standard error of the mean (sχ̄) concentration–response relationships of similarly bathed bronchial rings from the 8 SPAOPD-affected horses in the absence of the endothelin (ET)-receptor antagonists (black triangles; control rings), in the presence of 10−5 M of the ETA–receptor antagonist BQ-123 (white circles), and in the presence of 10−5 M of the ETB antagonist IRL-1038 (white squares). The presence of the ETB-receptor antagonist significantly (*P = 0.001) decreased the overall contractile response of the rings to ET-1 compared with that for the control rings.
Figure 4
Figure 4
Determination of pA2 values using the Schild plot for the endothelin (ET)A-receptor antagonist BQ-123 for the unaffected horses (left panel) and the SPAOPD-affected horses (right panel). The point where the line intersects the abscissa is the pA2 value. The pA2 values did not differ significantly between the groups.
Figure 5
Figure 5
Determination of pA2 values using the Schild plot for the ETB-receptor antagonist IRL-1038 for the unaffected horses (left panel) and the SPAOPD-affected horses (right panel). The point where the line intersects the abscissa is the pA2 value. The pA2 value for the SPAOPD-affected horses was significantly greater (P < 0.05) than that for the unaffected horses.
Figure 6
Figure 6
Composite expression of messenger RNA (mRNA) for the entire lung of unaffected horses (white bar) and SPAOPD-affected horses (black bar) as determined by quantitative competitive reverse-transcription polymerase chain reaction for the endothelin (ET)B receptor and β-actin (with 8 samples tested independently from each group). Mean ± standard error of the mean (sχ̄) values (expressed as molecules of ETB mRNA/molecules of β-actin mRNA) for unaffected and SPAOPD-affected horses were found not to be significantly different by the unpaired 2-tailed Student’s t-test.
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