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
| Autor: | Mirjam Spaeth, Christa Stadlbauer, Gerhardt Preissler, Sonnaert Michel, H-S Hofmann, Markus Hoenicka, Svitlana Golovchenko, Michael Ried, Rudolf Hatz, C Schneider, Leonie Englert |
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| Rok vydání: | 2021 |
| Předmět: |
Endothelin Receptor Antagonists
Pulmonary and Respiratory Medicine medicine.drug_mechanism_of_action Ambrisentan Hypertension Pulmonary Vasodilation Pulmonary Artery Pharmacology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Humans Medicine Pharmacology (medical) 030212 general & internal medicine Macitentan Cyclic Nucleotide Phosphodiesterases Type 5 Pulmonary Arterial Hypertension business.industry Endothelin receptor antagonist Biochemistry (medical) Phosphodiesterase 5 Inhibitors Tadalafil Bosentan 030228 respiratory system chemistry Vardenafil business Phosphodiesterase 5 inhibitor medicine.drug |
| Zdroj: | Pulmonary Pharmacology & Therapeutics. 66:101985 |
| ISSN: | 1094-5539 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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