This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose-dependently inhibited the expression of ECM-related proteins induced by transforming growth factor β1 (TGF-β1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-β signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.
Animals ; Humans ; Male ; Mice ; Rats ; Extracellular Matrix Proteins ; Fibrosis ; Kidney ; Kidney Diseases ; Phosphodiesterase 5 Inhibitors ; Plasminogen Activator Inhibitor 1

Cavernous nerve injury is an important cause of erectile dysfunction (ED). Although protective nerve technology has been widely used in nerve-sparing radical prostatectomy (nsRP), the incidence of ED is still very high after surgery. The purpose of our study was to evaluate erectile function (EF) and penile length in the non-erectile state (PLNES) following scheduled phosphodiesterase 5 inhibitor (PDE5i), vacuum erectile device (VED) treatment, and combination therapy after nsRP. One hundred patients with localized prostate cancer and normal EF were randomized to scheduled PDE5i group, VED treatment group, a combined treatment group, and the control group without any intervention. The International Index of Erectile Function-5 (IIEF-5) scores and PLNES were evaluated after 6 months and 12 months of treatment. Sexual Encounter Profile (SEP-Question 2 and SEP-Question 3) were evaluated after 12 months of treatment. Ninety-one of the 100 randomized patients completed the study. We found that the 5 mg tadalafil once a day (OaD) combined with VED can help improve IIEF-5 scores in nsRP patients after both 6 months and 12 months. VED alone or combined with tadalafil OaD can help patients maintain PLNES. VED combined with tadalafil OaD can improve the rate of successful penetration (SEP-Question 2) after 12 months. There were no significant differences in the return to target EF after 12 months among the groups. No significant correlation was noted between the variables and return to target EF (IIEF ≥ 17), and between the variables and effective shortening of the patient's penis (shortening ≥ 1 cm) after 12 months of intervention.
Erectile Dysfunction ; Humans ; Male ; Penile Erection ; Phosphodiesterase 5 Inhibitors ; Prospective Studies ; Prostatectomy ; Prostatic Neoplasms ; Tadalafil ; Treatment Outcome ; Vacuum

Noninvasive low-intensity extracorporeal shockwave treatment (Li-ESWT) has been widely used to treat erection disorders. There is no clear information regarding either the selection of patients for the treatment or the treatment protocol. In this study, we aimed to investigate the efficacy of extracorporeal shockwave therapy in diabetic patients with severe erectile dysfunction (International Index of Erectile Function-5 [IIEF-5] scores of 5 to 7). Sixty-three diabetes mellitus patients with erectile dysfunction having IIEF-5 scores of 5 to 7 and not showing a recovery of potency despite phosphodiesterase type 5 inhibitor therapy for the past 6 months were included in the study. The patients were evaluated based on their IIEF-5 scores and Erection Hardness Scale scores. The IIEF-5 score (mean ± standard deviation [s.d.]) increased from 5.29 ± 1.67 to 5.56 ± 1.85, with a difference of 0.27 ± 0.18 (P > 0.05). The Erection Hardness Scale scores (mean ± s.d.), on the other hand, increased from 1.46 ± 0.50 to 1.48 ± 0.50, with a difference of 0.02 ± 0 (P > 0.05). In conclusion, the response to phosphodiesterase type 5 inhibitors did not change after extracorporeal shockwave treatment in diabetes mellitus patients with severe erectile dysfunction (IIEF-5 scores of 5 to 7).
Diabetes Mellitus ; Erectile Dysfunction ; Extracorporeal Shockwave Therapy ; Humans ; Male ; Penile Erection ; Phosphodiesterase 5 Inhibitors ; Treatment Outcome

Silent information regulator 2-related enzyme 1 (SIRT1) is an aging-related protein activated with aging. Herein, we evaluated the role of SIRT1 in aging-related erectile dysfunction. The expression of SIRT1 was modulated in aged Sprague-Dawley rats following intragastric administration of resveratrol (Res; 5 mg kg^-1), niacinamide (NAM; 500 mg kg^-1) or Res (5 mg kg^-1) + tadalafil (Tad; phosphodiesterase-5 [PDE5] inhibitor; 5 mg kg^-1) for 8 weeks. Then, we determined erectile function by the ratio of intracavernosal pressure (ICP)/mean systemic arterial pressure (MAP). Cavernosal tissues were extracted to evaluate histological changes, cell apoptosis, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP), the superoxide dismutase (SOD)/3,4-methylenedioxyamphetamine (MDA) level, and the expression of SIRT1, p53, and forkhead box O3 (FOXO3a) using immunohistochemistry, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL), enzyme-linked immunosorbent assays, and western blot analysis. Compared with the control, Res treatment significantly improved erectile function, reflected by an increased content of smooth muscle and endothelium, NO/cGMP and SOD activity, and reduced cell apoptosis and MDA levels. The effect of Res was improved by adding Tad. In addition, the protein expression of SIRT1 was increased in the Res group, accompanied by decreased p53 and FOXO3a levels. In addition, inhibition of SIRT1 by NAM treatment resulted in adverse results compared with Res treatment. SIRT1 activation ameliorated aging-related erectile dysfunction, supporting the potential of SIRT1 as a target for erectile dysfunction treatment.
Animals ; Male ; Rats ; Cyclic GMP/metabolism* ; Erectile Dysfunction/metabolism* ; Nitric Oxide/metabolism* ; Penile Erection ; Penis/pathology* ; Phosphodiesterase 5 Inhibitors/pharmacology* ; Rats, Sprague-Dawley ; Sirtuin 1/metabolism* ; Superoxide Dismutase/metabolism* ; Tumor Suppressor Protein p53/metabolism*

This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in ratsand its cellular and molecular mechanisms. The heart pressure-volume loop (P-V loop) analysis was used to detect the effects of PF-04449613 on rat left ventricular pressure-volume relationship, aortic pressures and peripheral vessel resistance in healthy rats. The Langendorff perfusion of isolated rat heart was used to explore the effects of PF-04449613 on heart contractility. The cardiomyocyte sarcoplasmic reticulum (SR) Ca
Animals ; Calcium/metabolism* ; Myocardial Contraction ; Myocytes, Cardiac/metabolism* ; Phosphodiesterase Inhibitors ; Phosphoric Diester Hydrolases ; Rats ; Ryanodine Receptor Calcium Release Channel ; Sarcoplasmic Reticulum

Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.
Animals ; Colitis ; Inflammatory Bowel Diseases/drug therapy* ; Phosphodiesterase 4 Inhibitors

OBJECTIVE: To investigate the inhibitory effects of novel phosphodiesterase 4 inhibitor ZL-n-91 to the proliferation of leukemia cells L1210 and K562. METHODS: CCK-8 method was used to detect the effect of ZL-n-91 to the proliferation of L1210 and K562 cells, and the proliferation rate, IC RESULTS: ZL-n-91 showed a significant inhibitory effect to the proliferation of leukemia cells L1210 and K562 in a dose-dependent manner (P<0.001). After treated by ZL-n-91, the leukemia cells L1210 and K562 in the S-phase in cell cycle decreased significantly compared with those in control group (P<0.01). The apoptosis of leukemia cells L1210 and K562 could be induced by ZL-n-91 (P<0.001), and the expression level of apoptosis related protein BAX significantly increased. In the animal experiment, the result showed that ZL-n-91 could significantly inhibit the growth of subcutaneously transplantation tumor (P<0.05). CONCLUSION The novel phosphodiesterase 4 inhibitor ZL-n-91 can effectively inhibit the proliferation of leukemia cells L1210 and K562, which has the potential of anti-leukemia drug development.
Animals ; Cell Proliferation ; Humans ; K562 Cells ; Leukemia ; Mice ; Mice, Nude ; Phosphodiesterase 4 Inhibitors/pharmacology*

Obesity is a major public health issue worldwide and is frequently associated with erectile dysfunction (ED). Both conditions may share an internal pathologic environment, also known as common soil. Their main pathophysiologic processes are oxidative stress, inflammation, and resultant insulin and leptin resistance. Moreover, the severity of ED is correlated with comorbid medical conditions, including obesity. Therefore, amelioration of these comorbidities may increase the efficacy of ED treatment with phosphodiesterase 5 inhibitors, the first-line medication for patients with ED. Although metformin was originally developed as an insulin sensitizer six decades ago, it has also been shown to improve leptin resistance. In addition, metformin has been reported to reduce oxidative stress, inflammatory response, and body weight, as well as improve ED, in animal and human studies. Moreover, administration of a combination of metformin and phosphodiesterase 5 inhibitors improves erectile function in patients with ED who have a poor response to sildenafil and are insulin resistant. Thus, concomitant treatment of metabolic derangements associated with obesity in patients with ED who are obese would improve the efficacy and reduce the refractory response to penile vasodilators. In this review, we discuss the connecting factors between obesity and ED and the possible combined treatment modalities.
Animals ; Body Weight ; Comorbidity ; Erectile Dysfunction ; Humans ; Inflammation ; Insulin ; Leptin ; Male ; Metformin ; Obesity ; Oxidative Stress ; Phosphodiesterase 5 Inhibitors ; Public Health ; Sildenafil Citrate ; Soil ; Vasodilator Agents

BACKGROUND AND OBJECTIVES: Udenafil, a new phosphodiesterase-5 inhibitor (PDE5i), has been used to treat erectile dysfunction. Given the proven benefit of PDE5i in pulmonary arterial hypertension (PAH), we evaluated serial hemodynamic changes after single udenafil administration to determine the appropriate therapeutic dose. METHODS: Eighteen patients were randomly allocated into one of 3 groups: placebo, udenafil 50 mg (U50), and udenafil 100 mg (U100). Diagnosis for inclusion was idiopathic PAH or PAH associated with connective tissue disease. Patients with any contraindication to PDE5i, and/or PDE5i treatment in the past 1 month were excluded. Continuous hemodynamic monitoring was performed by placing a Swan-Ganz catheter. Information on cardiac index (CI), mean pulmonary arterial pressure (mPAP), mean systemic arterial pressure (mSAP), pulmonary arterial wedge pressure (PAWP), and pulmonary vascular resistance index (PVRI) was obtained for 4 hours after drug administration. RESULTS: The mPAP significantly decreased in both the U50 and U100 (−11 mmHg and −8 mmHg from baseline, respectively, p < 0.1). The mSAP also decreased in both U50 and U100; however, the decrease was greater in the U100 (Δ=−8.5 mmHg and Δ=−14.0 mmHg). CI increased in the U50, but decreased in the U100. Although PVRI decreased in both, statistical significance was only achieved in the U50 compared to placebo. PAWP was stable during monitoring. U50 had at least 4 hour-effect after administration. Only 2 patients with U100 experienced mild adverse events. CONCLUSIONS: This is the first demonstration of the acute hemodynamic changes induced by udenafil. U50 is considered an optimal dose for treating PAH with more than 4-hour treatment effect. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01553721.
Arterial Pressure ; Catheters ; Connective Tissue Diseases ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Diagnosis ; Erectile Dysfunction ; Hemodynamics ; Humans ; Hypertension ; Hypertension, Pulmonary ; Male ; Phosphodiesterase 5 Inhibitors ; Pulmonary Wedge Pressure ; Vascular Resistance

Cells, Cultured ; Cyclic Nucleotide Phosphodiesterases, Type 2 ; antagonists & inhibitors ; metabolism ; Fibroblasts ; drug effects ; metabolism ; Glucosides ; pharmacology ; Humans ; Lung ; cytology ; embryology ; Phenols ; pharmacology ; Phosphodiesterase Inhibitors ; pharmacology ; Tumor Suppressor Protein p53 ; metabolism