Abstract
Purpose
Both sildenafil and bosentan have been used clinically to treat pulmonary arterial hypertension. As these substances target different pathways to modulate vasoconstriction, we investigated the combined effects of both drug classes in isolated human pulmonary vessels.
Methods
Segments of pulmonary arteries (PA) and veins (PV) were harvested from 51 patients undergoing lobectomy. Contractile force was determined isometrically in an organ bath. Vessels were constricted with norepinephrine (NE) to determine effects of sildenafil. They were constricted with ET-1 to assess effects of bosentan, and with NE and ET-1 to evaluate the combination of both substances.
Results
Sildenafil (1E-5 M) significantly reduced maximum constriction by NE of both PA (13.0 ± 11.1 vs. 34.9 ± 7.6 % relative to KCl induced constriction; n = 6; p < 0.001) and PV (81.2 ± 34.2 vs 121.6 ± 20.8 %; n = 6; p < 0.01) but did not affect basal tones. Bosentan (1E-5 M) significantly reduced maximum constriction of PV (56.6 ± 21.5 vs. 172.1 ± 30.0 %; n = 6; p < 0.01) by ET-1 and led to a small but insignificant decrease of basal tone (p = 0.07). Bosentan almost completely abolished constriction of PA (1.0 ± 0.9 vs. 74.7 ± 25.7 %; n = 6; p < 0.001) by ET-1, but did not affect basal tone. Bosentan (1E-7 M) significantly attenuated combined ET-1/NE dose–response curves in PA (93.1 ± 47.4 vs. 125.3 ± 41.0 %; n = 12; p < 0.001) whereas the effect of sildenafil (1E-5 M) was less pronounced (103.6 ± 20.2 %; p < 0.05). Simultaneous administration of both substances showed a significantly greater reduction of maximum constriction in PA compared to individual administration (64.6 ± 26.3 %; p < 0.001).
Conclusions
Sildenafil only at its highest concentration was effective in suppressing NE induced pulmonary vessel contraction. Bosentan was able to completely suppress ET-1 induced contraction of PA and strongly attenuated contraction of PV. The present data suggest a benefit of sildenafil/bosentan combination therapy as they affect different pathways and may allow lower dosages.
Similar content being viewed by others
References
Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336:111–7.
Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–72.
Voswinckel R, Hoeper MM, Kramm T, Ghofrani HA. Right heart failure in chronic pulmonary hypertension and acute pulmonary embolism. Internist (Berl). 2012;53(5):545–56.
Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol. 2012;12:1401–5.
Holm P, Franco-Cereceda A. Tissue concentration of endothelins and functional effects of endothelin-receptor activation in human arteries and veins. J Thorac Cardiovasc Surg. 1996;112:264–72.
Ghofrani HA, Grimminger F. Treatment of pulmonary arterial hypertension: phosphodiesterase-5 inhibitors. Dtsch Med Wochenschr. 2006;8(131):311–4.
Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493–537.
Price LC, Wort SJ, Finney SJ, Marino PS, Brett SJ. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14:R169.
Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary hypertension. Eur Resp J. 2004;24:1007–10.
Hoeper MM, Granton J. Intensive care unit management of patients with severe pulmonary hypertension and right heart failure. Am J Respir Crit Care Med. 2011;184:1114–24.
Ghofrani HA, Olschewski H, Seeger W, Grimminger F. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie. 2002;56(11):665–72.
Rubin LJ. Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci. 2012;15:517–21.
Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43–50.
Hoenicka M, Lehle K, Jacobs VR, Schmid FX, Birnbaum DE. Properties of the human umbilical vein as a living scaffold for a tissue-engineered vessel graft. Tissue Eng. 2007;13:219–29.
Hoenicka M, Wiedemann L, Puehler T, Hirt S, Birnbaum DE, Schmid C. Effects of shear forces and pressure on blood vessel function and metabolism in a perfusion bioreactor. Ann Biomed Eng. 2010;38:3706–23.
Hoenicka M, Keyser A, Rupprecht L, Puehler T, Hirt S, Schmid C. Endothelium-dependent vasoconstriction in isolated vessel grafts: a novel mechanism of vasospasm? Ann Thorac Surg. 2011;92(4):1299–306.
Barnett CF, Machado RF. Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Manag. 2006;2(4):411–22.
Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res. 2003;93(4):280–91.
Omori K, Kotera J. Overview of PDEs and their regulation. Circ Res. 2007;100(3):309–27.
Sun XZ, Li ZF, Liu Y, Fang P, Li MX. Inhibition of cGMP phosphodiesterase 5 suppresses matrix metalloproteinase-2 production in pulmonary artery smooth muscles cells. Clin Exp Pharmacol Physiol. 2010;37(3):362–7.
Toque HA, Teixeira CE, Priviero FB, Morganti RP, Antunes E, De Nucci G. 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(4):787–96.
Zhao L, Mason NA, Morrell NW, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001;104(4):424–8.
Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360:895–900.
Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo controlled study. Lancet. 2001;358:1119–23.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903.
Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:62S–7S.
Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Resp J. 2004;24(3):353–9.
Acknowledgments
Experimental investigations were financially supported by a grant of Actelion (Allschwil, Switzerland). The authors appreciate the technical assistance of Mrs. K. Bielenberg.
Conflict of interest
All authors declare that there is no conflict of interest. All authors have read and approved the submitted version of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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 28, 45–51 (2014). https://doi.org/10.1007/s10557-013-6499-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-013-6499-0