评估内皮素受体拮抗剂（ERA）和磷酸二酯酶-5 抑制剂联合治疗在体外器官浴模型中病理性人肺动脉高压（PAH）的疗效。

Evaluation of the combination of endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension (PAH) in pathologic human pulmonary arteries in an ex-vivo organ bath model.

机构信息

Department of Thoracic Surgery, University Medical Center Regensburg, Germany.

出版信息

Pulm Pharmacol Ther. 2021 Feb;66:101985. doi: 10.1016/j.pupt.2020.101985. Epub 2020 Dec 24.

DOI:10.1016/j.pupt.2020.101985

PMID:33359621

Abstract

PURPOSE

Medical combination therapy of pulmonary arterial hypertension (PAH) may alleviate the drawbacks of monotherapy by avoiding drug tolerance and by increasing effectiveness, as shown by the combination of ambrisentan and tadalafil (AMBITION trial). The present ex-vivo study evaluated the combination of the endothelin receptor antagonists (ERA) macitentan and bosentan with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil in pulmonary arteries from patients suffering from terminal lung disease as a model of PAH.

METHODS

Segments of the pulmonary vessels were excised from resected lungs of patients requiring lung transplantation (LTX). Contraction of pulmonary arteries (PA) was elicited by consecutive dose-response curves of endothelin-1 (ET-1) followed by norepinephrine (NE) to allow inhibition by different pathways. Forces were measured isometrically in an organ bath in the presence and absence of ERA and PDE-5 inhibitors and their combination.

RESULTS

PA of 38 patients were examined between October 2016 and November 2019. Bosentan (1E-7 M) and macitentan (1E-8 M, 3E-8 M, 1E-7 M) inhibited ET-1 induced contractions, whereas vardenafil (1E-6 M, 3E-6 M, 1E-5 M) inhibited only the NE induced part of the contractions. Vardenafil enhanced bosentan-induced inhibition of vasoconstriction in a dose-dependent fashion. Combination effects exceeded single bosentan at 3E-6 M and 1E-5 M vardenafil, and they exceeded single vardenafil at the lower vardenafil concentrations. Macitentan showed a more pronounced inhibition than bosentan regardless of the lower concentrations. Accordingly, combination effects with vardenafil resembled those of macitentan alone.

CONCLUSIONS

Macitentan and bosentan were potent antagonists of vasoconstriction in PA of LTX patients. The benefit of drug combinations was demonstrated at selected concentrations only owing to a narrow therapeutic range of vardenafil in this ex-vivo model. These results suggest the utility of drug combinations other than the established pair of ambrisentan and tadalafil in PAH treatment but also make a case for a further assessment of vasodilator properties of drugs complementing ERA.

摘要

目的

肺动脉高压（PAH）的联合医学治疗可能通过避免药物耐受和提高疗效来缓解单药治疗的缺点，如安贝生坦联合他达拉非（AMBITION 试验）所示。本体外研究评估了内皮素受体拮抗剂（ERA）马西替坦和波生坦与磷酸二酯酶-5（PDE-5）抑制剂伐地那非在终末期肺病患者的肺血管中的组合，这些患者作为 PAH 的模型。

方法

从需要肺移植（LTX）的患者切除的肺中切除肺血管段。通过连续的内皮素-1（ET-1）剂量反应曲线和去甲肾上腺素（NE）来引起肺血管（PA）的收缩，以允许通过不同途径进行抑制。在存在和不存在 ERA 和 PDE-5 抑制剂及其组合的情况下，在器官浴中通过等距测量力。

结果

2016 年 10 月至 2019 年 11 月期间检查了 38 名患者的 PA。波生坦（1E-7 M）和马西替坦（1E-8 M、3E-8 M、1E-7 M）抑制 ET-1 诱导的收缩，而伐地那非（1E-6 M、3E-6 M、1E-5 M）仅抑制 NE 诱导的收缩部分。伐地那非以剂量依赖的方式增强了波生坦诱导的血管收缩抑制作用。组合效应在 3E-6 M 和 1E-5 M 伐地那非时超过了单药波生坦，在较低的伐地那非浓度时超过了单药伐地那非。无论浓度较低，马西替坦的抑制作用都比波生坦更明显。因此，与单独使用马西替坦相比，与伐地那非的组合作用相似。