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.

Publikationsverlauf

Eingereicht: 30. September 2020

Angenommen: 08. Dezember 2020

Artikel online veröffentlicht:
20. Januar 2021

• Literaturverzeichnis

• 1 Simonneau G, Gatzoulis MA, Adatia I. et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D34-D41
• 2 Voswinckel R, Hoeper MM, Kramm T. et al. Rechtsherzversagen bei chronischer pulmonaler Hypertonie und akuter Lungenembolie. Internist (Berl) 2012; 53: 545-556
• 3 Rubin LJ. Primary Pulmonary Hypertension. N Engl J Med 1997; 336: 111-117
• 4 Frost AE, Farber HW, Barst RJ. et al. Demographics and outcomes of patients diagnosed with pulmonary hypertension with pulmonary capillary wedge pressures 16 to 18 mm Hg: insights from the REVEAL Registry. Chest 2013; 143: 185-195
• 5 Galiè N, Humbert M, Vachiery J-L. et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67-119
• 6 Barst RJ, Rubin LJ, Long A. et al. A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension. N Engl J Med 1996; 334: 296-302
• 7 Channick RN. Combination therapy in pulmonary arterial hypertension. Am J Cardiol 2013; 111: 16C-20C
• 8 Toque HA, Teixeira CE, Priviero FBM. et al. Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. Br J Pharmacol 2008; 154: 787-796
• 9 Karasu-Minareci E, Ozbudak IH, Ozbilim G. et al. Acute effects of vardenafil on pulmonary artery responsiveness in pulmonary hypertension. ScientificWorldJournal 2012; 2012: 718279
• 10 Corbin JD, Beasley A, Blount MA. et al. Vardenafil: structural basis for higher potency over sildenafil in inhibiting cGMP-specific phosphodiesterase-5 (PDE5). Neurochem Int 2004; 45: 859-863
• 11 Gatfield J, Mueller Grandjean C, Sasse T. et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS ONE 2012; 7: e47662
• 12 Sidharta PN, van Giersbergen PLM, Halabi A. et al. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol 2011; 67: 977-984
• 13 Englert L, Stadlbauer C, Spaeth M. et al. 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. [under Review]
• 14 Ried M, Neu R, Lehle K. et al. Superior vasodilation of human pulmonary vessels by vardenafil compared with tadalafil and sildenafil: additive effects of bosentan. Interact Cardiovasc Thorac Surg 2017; 25: 254-259
• 15 Hoenicka M, Golovchenko S, Englert L. et al. Combination Therapy of Pulmonary Arterial Hypertension with Vardenafil and Macitentan Assessed in a Human Ex Vivo Model. Cardiovasc Drugs Ther 2019; 33: 287-295
• 16 Ried M, Potzger T, Neu R. et al. Combination of sildenafil and bosentan for pulmonary hypertension in a human ex vivo model. Cardiovasc Drugs Ther 2014; 28: 45-51
• 17 Pollock DM, Keith TL, Highsmith RF. Endothelin receptors and calcium signaling. FASEB J 1995; 9: 1196-1204
• 18 Davie NJ, Schermuly RT, Weissmann N. et al. The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studies. Eur J Clin Invest 2009; 39 (Suppl. 02) 38-49
• 19 Gao Y, Chen T, Raj JU. Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension. Am J Respir Cell Mol Biol 2016; 54: 451-460
• 20 Channick RN, Simonneau G, Sitbon O. et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study. The Lancet 2001; 358: 1119-1123
• 21 Ghofrani HA, Grimminger F. Therapie der pulmonalarteriellen Hypertonie: Phosphodiesterase-5-Inhibitoren. Dtsch Med Wochenschr 2006; 131: S311-S314
• 22 Corbin JD, Beasley A, Blount MA. et al. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 2005; 334: 930-938
• 23 Wharton J, Strange JW, Møller GMO. et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005; 172: 105-113
• 24 Murad F. Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest 1986; 78: 1-5
• 25 Amin A, Mohamadifar A, Taghavi S. et al. Lower Doses of Bosentan in Combination With Sildenafil Might be Beneficial in Pulmonary Arterial Hypertension. Res Cardiovasc Med 2015; 4: e26487
• 26 McLaughlin V, Channick RN, Ghofrani H-A. et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J 2015; 46: 405-413
• 27 Dardi F, Manes A, Palazzini M. et al. Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: real-world insights. Eur Respir J 2015; 46: 414-421
• 28 Sitbon O, Sattler C, Bertoletti L. et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J 2016; 47: 1727-1736
• 29 Pulido T, Adzerikho I, Channick RN. et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809-818
• 30 Jansa P, Pulido T. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial. Am J Cardiovasc Drugs 2018; 18: 1-11
• 31 Kwapiszewska G, Hoffmann J, Kovacs G. et al. Pulmonal (arterielle) Hypertonie. Pneumologie 2016; 70: 630-637
• 32 Humbert M, Morrell NW, Archer SL. et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 13S-24S
• 33 Stacher E, Graham BB, Hunt JM. et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 261-272
• 34 Rosenfeldt FL, He GW, Buxton BF. et al. Pharmacology of coronary artery bypass grafts. Ann Thorac Surg 1999; 67: 878-888