Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91^phox expression in porcine pulmonary artery endothelial cells

Article

Author: Jeremy, Jamie Y. ; Angelini, Gianni D. ; Srivastava, Amit ; Muzaffar, Saima ; Shukla, Nilima

Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O2•−) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP‐mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO‐mediated inhibition of NADPH oxidase. Therefore, the effect of sildenafil citrate and NO‐donating sildenafil (NCX 911) on O2•− formation and gp91phox (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs).

PAECs were incubated with 10 nM TXA2 analogue, 9,11‐dideoxy‐9α,11α‐methanoepoxy‐prostaglandin F2α (U46619) (±sildenafil or NCX 911), for 16 h and O2•− formation measured spectrophometrically and gp91phox using Western blotting. The role of the NO‐cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN‐1), the diethylamine/NO complex (DETA‐NONOate), the guanylyl cyclase inhibitor, 1H‐{1,2,4}oxadiazolo{4,3‐a}quinoxalin‐1‐one (ODQ), and the protein kinase G inhibitor, 8‐bromoguanosine‐3′,5′‐cyclic monophosphorothioate, Rp‐isomer (Rp‐8‐Br‐cGMPS). NO release was studied using a fluorescence assay and O2•−–NO interactions by measuring nitrites.

After a 16‐h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration‐dependent inhibition of O2•− formation and gp91phox expression, NCX 911 being more potent (IC50; 0.26 nM) than sildenafil citrate (IC50; 1.85 nM). These inhibitory effects were reversed by 1 μM ODQ and 10 μM Rp‐8‐Br‐cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell‐free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 μM SIN‐1 and blocked partially by the eNOS inhibitor 10 μMN5‐(1‐iminoethyl)‐ornithine (L‐NIO). Acutely, sildenafil and NCX 911 also inhibited O2•− formation, again blocked by 1 μM ODQ. NCX 911 reacted with O2•− generated by xanthine oxidase, an effect that was inhibited by superoxide dismutase (500 U ml−1).

Since O2•− formation plays contributory role in ARDS, both sildenafil citrate and NCX 911 may be indicated for treating ARDS through suppression of NADPH oxidase expression and therefore of O2•− formation and preservation of NO bioavailability.

British Journal of Pharmacology (2005) 146, 109–117. doi:10.1038/sj.bjp.0706305

01 Jul 2005·European Journal of PharmacologyQ3 · MEDICINE

Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits

Q3 · MEDICINE

Article

Author: Raj Persad ; Nilima Shukla ; Robert Jones ; Jamie Y. Jeremy ; Gianni D. Angelini

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.

01 Jan 2005·The Journal of Sexual MedicineQ2 · MEDICINE

A Nitric Oxide-Releasing PDE5 Inhibitor Relaxes Human Corpus Cavernosum in the Absence of Endogenous Nitric Oxide

Q2 · MEDICINE

Article

Author: Minhas, Suks ; Bellringer, James ; Thomas, Phil ; Ralph, David J. ; Kell, Phil D. ; Cellek, Selim ; Kalsi, Jasjit S.

ABSTRACTIntroductionIn conditions with severe deficiency of endogenous nitric oxide (NO), such as long-term diabetes and cavernosal nerve injury, phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in the treatment of erectile dysfunction. NO-releasing PDE5 inhibitors could be an alternative therapeutic approach in such cases.AimWe therefore aimed to compare sildenafil and NO-releasing sildenafil (NCX-911) in relaxing human corpus cavernosum in the absence or presence of endogenous NO.MethodsThe two compounds were compared in reducing the phenylephrine-induced tone of human corpus cavernosum in the presence or absence of an inhibitor of NO synthase (L-NAME; 500 µM) or an inhibitor of soluble guanylate cyclase (ODQ, 10 µM).ResultsNCX-911 was as potent as sildenafil in control conditions (EC50 = 733.1 ± 94.4 nM and 800.7 ± 155.8 nM, respectively). The potency of NCX-911 was not altered but that of sildenafil decreased significantly in the presence of L-NAME (EC50 = 980.4 ± 106.7 nM and 2446.7 ± 256.8 nM, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 µM failed to induce relaxation in the presence of ODQ (EC50 = 6578 ± 1150 nM and 6488 ± 938 nM for NCX-911 and sildenafil, respectively).ConclusionThese results show that the potency of NCX-911 was maintained unlike sildenafil in the absence of endogenous NO confirming the potential use of NO-releasing PDE5 inhibitors in NO-deficient conditions.

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Indication	Highest Phase	Country/Location	Organization	Date
Erectile Dysfunction	Preclinical	France	Nicox SA	-

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