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

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 TXA(2) analogue 9,11-dideoxy-9 alpha 11 alpha-methanoepoxy ProstaglandinF(2) (U46619, 0.5 mu M) increased vessel tone (32.48 +/- 1.5 vs 13.13 +/- 0.56 mmHg; n = 12). 2NTX-99 (0.1-100 mu M: n = 5), caused a concentration-dependent relaxation, prevented by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 mu M, n = 4), an inhibitor of soluble guanylate cyclase. Acetylcholine (0.1-10 mu M; n = 3) and a reference NO-donor, isosorbide-5-mononitrate (5-100 mu M; n = 4), were ineffective. Intraluminal perfusion of washed human platelets (2 x 10(8) cells/ml) increased intravascular pressure after challenge with arachidonic acid (AA, 2 mu W: n = 5), an increase abolished by acetylsalicylic acid and significantly reduced by 2NTX-99 (40 mu M; n = 5). TXB2 in the lung perfusate was detected after platelet activation, 2NTX-99 inhibited TXA(2) 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 mu M; n = 6), U46619 (0.001-3 mu M, n = 3) or LTD4 (1 pM-1 mu M; n = 6). 2NTX-99 vasodilates the pulmonary vasculature via the release of nitric oxide (NO) and reduces intraluminal, AA-induced, TXA(2) formation. The combined activity of 2NTX-99 as an NO-donor and a TXA(2)-synthesis inhibitor provides strong support for its potential therapeutic use in pathologies of the pulmonary vascular bed (e.g. pulmonary hypertension). (C) 2012 Elsevier Inc. All rights reserved.