Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ET_B-receptor expression levels

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• 作者：Sté ; phanie Sauvageau ; Eric Thorin ; Louis Villeneuve ; Jocelyn Dupuis
• 关键词：Endothelin ; Endothelin receptor antagonists ; Lung ; Pathophysiology ; Pharmacology ; Pulmonary hypertension ; Receptors
• 刊名：Pulmonary Pharmacology & Therapeutics
• 出版年：2009
• 出版时间：August 2009
• 年：2009
• 卷：22
• 期：4
• 页码：311-317
• 全文大小：510 K

文摘

Background and purpose

The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension.

Experimental approach

ET-1 levels were quantified by ELISA. PreproET-1, ET_A and ET_B receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ET_A (A-147627), ET_B (A-192621) and dual ET_A/B (bosentan) receptor antagonists.

Key results

In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced (p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ET_B receptor (p < 0.001) gene expressions were reduced, as were ET_B receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ET_A or the ET_B receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ET_A receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).

Conclusions and implications

The effectiveness of both selective ET_A and dual ET_A/B receptor antagonists is markedly increased in PAH. Down-regulation of pulmonary resistance arteries ET_B receptor may contribute to this finding.