title: The pulmonary pharmacology of [4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide] (2NTX-99), an anti-atherotrombotic compound with therapeutic potential in pathological conditions that target lung vasculature.
abstract: The pharmacological activity of 2NTX-99 ([4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide]) was investigated in vitro in the intact, rat pulmonary vasculature and in guinea pig airways. Rat lungs were perfused at constant flow and changes in vascular tone recorded. Challenge with the TXA₂ analogue 9,11-dideoxy-9α11α-methanoepoxy ProstaglandinF₂ (U46619, 0.5 μM) increased vessel tone (32.48±1.5 vs 13.13±0.56 mmHg; n=12). 2NTX-99 (0.1-100 μM; n=5), caused a concentration-dependent relaxation, prevented by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 μM, n=4), an inhibitor of soluble guanylate cyclase. Acetylcholine (0.1-10 μM; n=3) and a reference NO-donor, isosorbide-5-mononitrate (5-100 μM; n=4), were ineffective. Intraluminal perfusion of washed human platelets (2 × 10⁸ cells/ml) increased intravascular pressure after challenge with arachidonic acid (AA, 2 μM; n=5), an increase abolished by acetylsalicylic acid and significantly reduced by 2NTX-99 (40 μM; n=5). TXB₂ in the lung perfusate was detected after platelet activation, 2NTX-99 inhibited TXA₂ synthesis (6.45±0.6 and 1.10±0.2 ng/ml, respectively). 2NTX-99 did not alter central or peripheral airway responsiveness to Histamine (0.001-300 μM; n=6), U46619 (0.001-3 μM, n=3) or LTD₄ (1 pM-1 μM; n=6). 2NTX-99 vasodilates the pulmonary vasculature via the release of nitric oxide (NO) and reduces intraluminal, AA-induced, TXA₂ formation. The combined activity of 2NTX-99 as an NO-donor and a TXA₂-synthesis inhibitor provides strong support for its potential therapeutic use in pathologies of the pulmonary vascular bed (e.g. pulmonary hypertension).
authors.affiliation: Department of Pharmacological Sciences, School of Pharmacy, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Brivio
authors.forename: C
authors.initials: C
authors.lastname: Buccellati
authors.forename: F
authors.initials: F
authors.lastname: Fumagalli
authors.forename: J
authors.initials: J
authors.lastname: Hodge
authors.forename: C
authors.initials: C
authors.lastname: Casagrande
authors.forename: G C
authors.initials: GC
authors.lastname: Folco
authors.forename: A
authors.initials: A
authors.lastname: Sala
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D013927:Thrombosis / Q000188:drug therapy*; D013929:Thromboxane B2 / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
chemical_list: C510792:4-methoxy-N'-(4-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide; D001549:Benzamides; D013929:Thromboxane B2