title: Combination of sildenafil and bosentan for pulmonary hypertension in a human ex vivo model.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Thoracic Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany, micha.ried@t-online.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Ried
authors.forename: Tobias
authors.initials: T
authors.lastname: Potzger
authors.forename: Reiner
authors.initials: R
authors.lastname: Neu
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sziklavari
authors.forename: Tamas
authors.initials: T
authors.lastname: Szöke
authors.forename: Andreas
authors.initials: A
authors.lastname: Liebold
authors.forename: Hans-Stefan
authors.initials: HS
authors.lastname: Hofmann
authors.forename: Markus
authors.initials: M
authors.lastname: Hoenicka
mesh_terms: D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D009638:Norepinephrine / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D000077300:Bosentan; D009638:Norepinephrine