Organbadversuche an humanen Pulmonalgefäßen: Beurteilung der Medikamentenwirkung zur Behandlung der pulmonalarteriellen Hypertonie

Zusammenfassung

In der Therapie der pulmonalarteriellen Hypertonie (PAH) kommen zahlreiche Medikamentenklassen zum Einsatz, u. a. Endothelinrezeptorantagonisten (ERA) und Phosphodiesterase-5-(PDE-5-)Inhibitoren. In einem humanen Ex-vivo-Modell sollte überprüft werden, ob durch die Kombination zweier Substanzklassen ein höherer Effekt erzielt werden kann oder – bei gleichem Effekt – eine niedrigere Dosierung der Einzelsubstanzen ausreicht. Wir etablierten ein Organbadmodell, welches uns die In-vitro-Untersuchung der dosisabhängigen Effekte von ERA und PDE-5-Inhibitoren auf die durch Norepinephrin und Endothelin-1 induzierte Kontraktilität humaner Pulmonalgefäße sowie den Vergleich von Mono- und Dualtherapie ermöglichte. Auch wenn die Übertragung der Ex-vivo-Daten auf die Situation im Patienten mit Vorsicht erfolgen muss, so hat sich das Organbad dennoch als hilfreiches Instrument zur Evaluation der dosisabhängigen Effekte von ERA, PDE-5-Inhibitoren und deren Kombination erwiesen. Die Wirksamkeit der Kombinationstherapie und das Potenzial zur Dosisreduktion waren in diesem Modell abhängig von den verwendeten Konzentrationen und vom Einfluss der Vorerkrankungen auf die Blutgefäßfunktion. Diese Arbeit beschreibt die bisherigen und wichtigsten Ergebnisse unserer experimentellen Untersuchungen und gibt einen Ausblick auf zukünftige Projekte.

Abstract

Various vasodilator medications are used in the treatment of pulmonary arterial hypertension (PAH), such as endothelin receptor antagonists (ERA) or phosphodiesterase-5-(PDE-5-)inhibitors. In a human ex vivo model, we investigated whether the combination of two substance classes could achieve a higher effect or – without loss of vasodilatation – a lower dosage of the individual substances might be sufficient. We established an ex vivo organ bath model to evaluate the dose-dependent effects of ERA and PDE-5-inhibitors on pulmonary vessels harvested from patients who underwent surgery (lung resection/transplantation). We compared the combined use of both substance classes with administration of one class of drugs alone. Due to the limitations of the experimental design, it is not possible to extrapolate our results to the conditions in vivo. Nevertheless, organ bath proved to be helpful in evaluating the dose-dependent effects of ERA and PDE-5 inhibitors, which is not practical in everyday clinical practice. In this setting, the effectiveness of the combination therapy and the potential for dose reduction depended on the concentrations used and on the influence of previous illnesses on blood vessel function. This article describes the most important results of our experimental investigations and suggestions for future projects.

Publication History

Received: 30 September 2020

Accepted: 08 December 2020

Article published online:
20 January 2021

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