Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment

Silva, Fábio H.; Karakus, Serkan; Musicki, Biljana; Matsui, Hotaka; Bivalacqua, Trinity J.; Santos, Jean Leandro dos; Costa, Fernando Ferreira; Burnett, Arthur L.

doi:10.1124/jpet.116.235473

Cited by 30 publications

(72 citation statements)

References 38 publications

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“…Immunoblot analyses with antibodies that selectively recognize P-PDE5A (Ser-92) and PDE5A, respectively, showed that P-PDE5 (Ser-92) and PDE5 protein expressions were significantly reduced (P<0.05) in the penis of vehicle-treated Sickle compared to vehicle-treated WT mice (Fig. 3), consistent with our previous reports (Champion et al 2005, Bivalacqua et al 2007, Lagoda et al 2013, Silva et al 2016). Testosterone treatment of Sickle mice significantly (P<0.05) increased P-PDE5 (Ser-92) and PDE5 protein expressions to levels comparable to WT levels, indicating that testosterone completely normalized downregulated PDE5 activation and protein expression in the Sickle mouse penis.…”

Section: Resultssupporting

confidence: 91%

“…2C) and poststimulated ICP/MAP area (Fig. 2D) were significantly (P<0.05) higher in vehicle-treated Sickle compared with vehicle-treated WT mice after cavernous nerve electrical stimulation was terminated, consistent with our previous report (Silva et al 2016). Testosterone completely normalized (P<0.05) detumescence time/MAP and poststimulated ICP/MAP area in Sickle mice, indicating correction of prolonged poststimulation erectile responses in these mice.…”

Section: Resultssupporting

confidence: 90%

“…2C) and post-stimulated ICP/ MAP area (Fig. 2D) were significantly (p < 0.05) higher in vehicle-treated Sickle compared with vehicle-treated WT mice after cavernous nerve electrical stimulation was terminated, consistent with our previous report (Silva et al, 2016). Testosterone Figure 1 Testosterone treatment restores serum testosterone levels (A) and seminal vesicles weight (B) in Sickle mice.…”

Section: Testosterone Treatment Reduces Prolonged Detumescence In Sicsupporting

confidence: 86%

“…Sickle mice exhibited an excessive post-cavernous nerve stimulation erectile response (prolonged detumescence) (this study and Silva et al, 2016). This excessive post-stimulation erectile response was completely reversed by testosterone treatment, suggesting decreased priapic activity in Sickle mice.…”

Section: Discussionmentioning

confidence: 64%

“…Reduced nitric oxide (NO)/cGMP bioavailability in the penis related to decreased endothelial NO synthase (eNOS) activity is a principal molecular defect underlying priapism in SCD (Champion et al, 2005;Bivalacqua et al, 2007Bivalacqua et al, , 2013Musicki et al, 2011;Lagoda et al, 2013). Basally low levels of eNOS and NO downstream signaling in the penis in SCD are associated with decreased phosphodiesterase (PDE)5 regulatory function due to lack of the cGMP-dependent feedback control mechanism, resulting in unchecked cGMP accumulation in the penis upon neurostimulation and priapism (Champion et al, 2005;Bivalacqua et al, 2007;Burnett, 2008;Lagoda et al, 2013;Sopko et al, 2015;Silva et al, 2016). Oxidative stress is also increased in the SCD penis associated with upregulation of NADPH oxidase and eNOS uncoupling (Kanika et al, 2010;Musicki et al, 2012;Bivalacqua et al, 2013), while the vasoconstrictive RhoA/Rho kinase signaling pathway is downregulated, further exacerbating priapism because of reduced vasoconstriction .…”

Section: Introductionmentioning

confidence: 99%

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Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis

Musicki¹,

Karakus²,

Akakpo³

et al. 2017

Andrology

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Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild-type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone-responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α-smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser-92, eNOS at Ser-1177, neuronal (n) NOS at Ser-1412, and Akt at Ser-473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P-PDE5 (Ser-92), PDE5, P-eNOS (Ser-1177), and P-Akt (Ser-473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P-nNOS (Ser-1412), eNOS, nNOS, or α-smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 90%

Section: Testosterone Treatment Reduces Prolonged Detumescence In Sicsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis

Musicki¹,

Karakus²,

Akakpo³

et al. 2017

Andrology

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TSPO ligand FGIN‐1‐27 controls priapism in sickle cell mice via endogenous testosterone production

Musicki

Karakus

Favor

et al. 2020

Journal Cellular Physiology

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Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN‐1‐27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase‐mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.

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Priapism caused by partial deficiency of tetrahydrobiopterin through hypofunction of the sympathetic neurons in sepiapterin reductase gene‐disrupted mice

Sumi‐Ichinose

Suganuma

Kano

et al. 2022

J of Inher Metab Disea

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6R‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH4) is an essential cofactor for aromatic L‐amino acid hydroxylases, including tyrosine hydroxylase (TH), alkylglycerol monooxygenase, and three types of nitric oxide (NO) synthases (NOS). Sepiapterin reductase (SPR) catalyzes the third step of BH4 biosynthesis. SPR gene‐disrupted (Spr−/−) mice exhibit a dystonic posture, low body weight, hyperphenylalaninemia, and unstable hypertension with endothelial dysfunction. In this study, we found that Spr−/− mice suffered from a high incidence of severe priapism. Their erections persisted for months. The biopterin, BH4, and norepinephrine contents, and TH protein levels in the penile tissue of Spr−/− mice without and with priapism were significantly reduced compared to those of Spr+/+ mice. In contrast, their neural NOS (nNOS) protein levels were increased, and the cyclic guanosine monophosphate (cGMP) levels were remarkably elevated in the penises of Spr−/− mice with priapism. The symptoms were relieved by repeated administration of BH4. The biopterin, BH4, and norepinephrine contents were increased in penile homogenates from BH4‐supplemented Spr−/− mice, and the TH protein levels tended to increase, and their nitrite plus nitrate levels were significantly lower than those of vehicle‐treated Spr−/− mice and were approximately the same as vehicle‐ and BH4‐supplemented Spr+/+ mice. Thus, we deduced that the priapism of Spr−/− mice is primarily caused by hypofunction of the sympathetic neurons due to cofactor depletion and the loss of TH protein and, further, dysregulation of the NO/cGMP signaling pathway, which would be caused by disinhibition of nNOS‐containing neurons and/or abnormal catabolism of cyclic nucleotides is suggested.

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Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment

Cited by 30 publications

References 38 publications

Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis

Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis

TSPO ligand FGIN‐1‐27 controls priapism in sickle cell mice via endogenous testosterone production

Priapism caused by partial deficiency of tetrahydrobiopterin through hypofunction of the sympathetic neurons in sepiapterin reductase gene‐disrupted mice

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