title: Antiserotonergic properties of terguride in blood vessels, platelets, and valvular interstitial cells.
abstract: Serotonin (5-hydroxytryptamine; 5-HT) is involved in heart valve tissue fibrosis, pulmonary arterial fibrosis, and pulmonary hypertension. We aimed at characterizing the antiserotonergic properties of the ergot alkaloid derivative terguride [1,1-diethyl-3-(6-methyl-8α-ergolinyl)urea] by using functional receptor assays and valvular interstitial cell culture. Terguride showed no vasoconstrictor effect in porcine coronary arteries (5-HT(2A) receptor bioassay) and no relaxant effect in porcine pulmonary arteries (5-HT(2B) receptor bioassay). Terguride behaved as a potent antagonist at 5-HT(2A) receptors (noncompetitive antagonist parameter pD'₂ 9.43) and 5-HT(2B) receptors (apparent pA₂ 8.87). Metabolites of terguride (N″-monodeethylterguride and 6-norterguride) lacked agonism at both sites. N″-monodeethylterguride and 6-norterguride were surmountable antagonists at 5-HT(2A) receptors (pA₂ 7.82 and 7.85, respectively) and 5-HT(2B) receptors (pA₂ 7.30 and 7.11, respectively). Kinetic studies on the effects of terguride in pulmonary arteries showed that the rate to reach drug-receptor equilibrium for terguride was fast. Washout experiments showed that terguride easily disappeared from the receptor biophase. Pretreatment with terguride inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC₅₀ 16 nM). In porcine valvular interstitial cells, 5-HT-induced activation of extracellular signal-regulated kinase (ERK) 1/2, an initiator of cellular proliferation and activity, was blocked by terguride as shown by Western blotting. In these cells, the stimulatory effect of 5-HT on [³H]proline incorporation (index of extracellular matrix collagen) was blocked by terguride. Because of the inhibition of both 5-HT(2A) and 5-HT(2B) receptors, platelet aggregation, and cellular proliferation and activity (ERK1/2 phosphorylation and collagen production) terguride may have therapeutic potential in the treatment of fibrotic disorders.
authors: Institute of Pharmacy, Free University of Berlin, Berlin, Germany.
authors: Alexandra
authors: A
authors: Kekewska
authors: Tilo
authors: T
authors: Görnemann
authors: Florian
authors: F
authors: Jantschak
authors: Erika
authors: E
authors: Glusa
authors: Heinz H
authors: HH
authors: Pertz
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001021:Aortic Valve / Q000166:cytology; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006351:Heart Valves / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007650:Ketanserin / Q000494:pharmacology; D007700:Kinetics; D008090:Lisuride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008943:Mitral Valve / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D034421:Sus scrofa; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D058830:Serotonin 5-HT2 Receptor Antagonists; C006208:dironyl; D012701:Serotonin; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D007650:Ketanserin; D008090:Lisuride; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3