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Comparative Study
. 2006 Jul;70(3):197-205.

Comparison of 2 endothelin-receptor antagonists on in vitro responses of equine palmar digital arterial and venous rings to endothelin-1

Ashley M Stokes  1 , Changaram S Venugopal, Giselle Hosgood, Susan C Eades, Rustin M Moore
Affiliations
Comparative Study

Comparison of 2 endothelin-receptor antagonists on in vitro responses of equine palmar digital arterial and venous rings to endothelin-1

Ashley M Stokes et al. Can J Vet Res. 2006 Jul.

Abstract
in English, French

The goals of this study were to determine the concentration-response (C-R) relationship of endothelin-1 (ET-1), compare 2 ET-receptor antagonists and determine the antagonist concentrations that block the vasomotor effects of ET-1, and compare the effectiveness of ET-1 and previously studied vasoconstrictors in equine palmar digital arterial and venous rings in vitro. Vessel rings from 8 nonlaminitic horses were placed in Tyrode's solution, 1 side fixed to the floor of an organ bath and the other side fixed to a force-displacement transducer. Two separate studies were conducted: (I) incubation with a single ET-receptor antagonist (PD142893 or PD145065 at a concentration of 10(-7), 10(-6), or 10(-5) M), followed by determination of an ET-1 C-R curve (using concentrations of 10(-10) to 10(-6) M) for medial vessel rings; and (II) comparison of ET-1 with norepinephrine and histamine (10(-10) to 10(-6) M) and comparison of contractile responses of medial and lateral vessel rings. In study I, ET-1 administration caused pronounced and sustained concentration-dependent contraction of vessel rings; these contractile responses were decreased by 10(-5) M PD142893 and were completely blocked by 10(-5) M PD145065. Venous rings had greater apparent maximum contraction in response to ET-1 than arterial rings. In study II, the relative sensitivity of norepinephrine was found to be equivalent to that of ET-1, whereas that of histamine was lower. No significant differences were observed between responses of medial versus lateral vessel rings. Thus, ET-1 is a potent vasoconstrictor of equine palmar digital arteries and veins, and the ET-receptor antagonist PD145065 is more effective than PD142893 in inhibiting these contractile effects in vitro.

Cette étude, effectuée in vitro en utilisant des anneaux vasculaires provenant de l’artère et de la veine digitale palmaire de chevaux, avait comme objectifs de déterminer la relation concentration–réponse (C–R) de l’endotheline-1 (ET-1), de comparer deux antagonistes des récepteurs à ET et déterminer les concentrations d’antagonistes qui bloquent les effets vasomoteurs d’ET-1, ainsi que de comparer l’efficacité d’ET-1 et de vasoconstricteurs préalablement étudiés. Des anneaux vasculaires provenant de huit chevaux sans boiterie ont été mis dans de la solution de Tyrode, un côté fixé au plancher d’un bain à organe et l’autre côté fixé à un transducteur de « force de déplacement ». Deux études distinctes ont été réalisées : (I) incubation avec un seul antagoniste de récepteur à ET (PD142893 ou PD145065 à une concentration de 10−7, 10−6 ou 10−5 M), suivi de la détermination de la courbe C–R d’anneaux vasculaires médiaux à ET-1 (concentrations de 10−10 à 10−6 M); et (II) comparaison d’ET-1 à la norépinéphrine et l’histamine (concentrations de 10−10 à 10−6 M) et comparaison des réponses contractiles d’anneaux vasculaires médiaux et latéraux. Dans l’étude I, l’administration d’ET-1 entraîna une contraction concentration-dépendante prononcée et soutenue des anneaux vasculaires; ces réponses contractiles étaient diminuées par 10−5 M de PD142893 et étaient complètement bloquées par 10−5 M de PD145065. Les anneaux veineux avaient une contraction maximale apparente plus grande que les anneaux artériels en réponse à ET-1. Dans l’étude II, la sensibilité relative de la norépinéphrine était équivalente à celle d’ET-1, alors que celle de l’histamine était inférieure. Aucune différence significative n’a été observée entre les réponses des anneaux vasculaires médiaux et latéraux. Ainsi, ET-1 est un vasoconstricteur puissant des artères et veines digitales palmaires de chevaux, et l’antagoniste du récepteur à ET-1 PD145065 est plus efficace que PD142893 pour inhiber ces effets contractiles in vitro.

(Traduit par Docteur Serge Messier)

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Figures

Figure 1
Figure 1
Mean (± standard error) concentration–response (C–R) curves for rings of equine palmar digital arteries (A) exposed to endothelin-1 (ET-1), 10−10 to 10−6 M, expressed in milligrams of tension per milligram of dry weight. Top panel: after incubation with PD142893, 10−7 to 10−5 M, or Tyrode’s solution (control). Bottom panel: after incubation with PD145065, 10−7 to 10−5 M, or Tyrode’s solution (control). Asterisks indicate significant differences (P < 0.05) in the apparent maximum contraction value between the controls and these molar concentrations of each ET-1 antagonist.
Figure 2
Figure 2
Mean C–R curves for veins (V), under the same conditions as for Figure 1.
Figure 3
Figure 3
Schild regressions comparing antagonist potency between PD142893 and PD145065 for arteries (A) and veins (V). Regression lines could not be accurately determined for the 10−7 M concentration of PD142893 for arteries or veins owing to potentiation of ET-1-induced vasoconstriction; therefore, pA2 values could not be calculated for PD142893 since this value is equal to the x-intercept of this calculated line.
Figure 4
Figure 4
Mean C–R curves of medial arteries (A) and veins (V) to the vasoconstrictors norepinephrine (NE), histamine (HST), and ET at concentrations of 10−10 to 10−6 M. Asterisks indicate significant differences (P < 0.05) in the apparent maximum contraction value from those for histamine.
Figure 5
Figure 5
Mean C–R curves of combined medial and lateral arteries (A) and veins (V) to norepinephrine and histamine at concentrations of 10−10 to 10−4 M. Asterisks indicate significant differences (P < 0.05) in the apparent maximum contraction value from those for histamine.
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