The pathogenesis of stroke is complex, with genetic risk factors as one of the main factors. The genetic variants of phosphodiesterase 4D (PDE4D) was significantly associated with the susceptibility to ischemic stroke (IS) in Caucasian population, but its association with the susceptibility to stroke in Chinese population is unclear. This article is intended to review the research on the association between PDE4D genetic variants and stroke susceptibility in Chinese population, aiming to further optimize the relevant research programs and provide reference for the prevention and treatment of stroke in China.
Humans ; Brain Ischemia/genetics* ; Genetic Predisposition to Disease ; East Asian People ; Cyclic Nucleotide Phosphodiesterases, Type 4/genetics* ; Stroke/genetics* ; Polymorphism, Single Nucleotide ; Risk Factors

Humans ; Colorectal Neoplasms/genetics* ; Esophageal Neoplasms ; Genetic Predisposition to Disease ; Genotype ; Phosphoinositide Phospholipase C/genetics* ; Polymorphism, Single Nucleotide

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

Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; MicroRNAs/genetics* ; Phospholipase C delta ; Prostatic Neoplasms/genetics*

Gα(q)-coupled receptor stimulation was implied in the activation process of transient receptor potential canonical (TRPC)1/4 and TRPC1/5 heterotetrameric channels. The inactivation occurs due to phosphatidylinositol 4,5-biphosphate (PI(4,5)P₂) depletion. When PI(4,5)P₂ depletion was induced by muscarinic stimulation or inositol polyphosphate 5-phosphatase (Inp54p), however, the inactivation by muscarinic stimulation was greater compared to that by Inp54p. The aim of this study was to investigate the complete inactivation mechanism of the heteromeric channels upon Gα(q)-phospholipase C β (Gα(q)-PLCβ) activation. We evaluated the activity of heteromeric channels with electrophysiological recording in HEK293 cells expressing TRPC channels. TRPC1/4 and TRPC1/5 heteromers undergo further inhibition in PLCβ activation and calcium/protein kinase C (PKC) signaling. Nevertheless, the key factors differ. For TRPC1/4, the inactivation process was facilitated by Ca²⁺ release from the endoplasmic reticulum, and for TRPC1/5, activation of PKC was concerned mostly. We conclude that the subsequent increase in cytoplasmic Ca²⁺ due to Ca²⁺ release from the endoplasmic reticulum and activation of PKC resulted in a second phase of channel inhibition following PI(4,5)P₂ depletion.
Calcium ; Cytoplasm ; Endoplasmic Reticulum ; GTP-Binding Proteins ; HEK293 Cells ; Inositol ; Phosphatidylinositol 4,5-Diphosphate ; Phospholipases ; Phosphotransferases ; Protein Kinase C ; Transient Receptor Potential Channels ; Type C Phospholipases

OBJECTIVE: We investigated the clinical characteristics of men with testosterone replacement therapy (TRT)-induced hypogonadism and its effect on assisted reproductive technology (ART) in infertile couples.METHODS: This study examined the records of 20 consecutive male patients diagnosed with azoospermia or severe oligozoospermia (<5×10⁶/mL) who visited a single infertility center from January 2008 to July 2018. All patients were treated at a primary clinic for erectile dysfunction or androgen deficiency symptoms combined with low serum testosterone. All men received a phosphodiesterase 5 inhibitor and TRT with testosterone undecanoate (Nebido®) or testosterone enanthate (Jenasteron®). Patients older than 50 years or with a chronic medical disease such as diabetes were excluded.RESULTS: The mean age of patients was 37 years and the mean duration of infertility was 16.3±11.6 months. At the initial presentation, eight patients had azoospermia, nine had cryptozoospermia, and three had severe oligozoospermia. Serum follicle-stimulating hormone levels were below 1.0 mIU/mL in most patients. Three ongoing ART programs with female factor infertility were cancelled due to male spermatogenic dysfunction; two of these men had normal semen parameters in the previous cycle. After withholding TRT, serum hormone levels and sperm concentrations returned to normal range after a median duration of 8 months.CONCLUSION: TRT with high-dose testosterone can cause spermatogenic dysfunction due to suppression of the hypothalamic-pituitary-testicular axis, with adverse effects on infertility treatment programs. TRT is therefore contraindicated for infertile couples attempting to conceive, and the patient's desire for fertility must be considered before initiation of TRT in a hypogonadal man.
Azoospermia ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Erectile Dysfunction ; Family Characteristics ; Female ; Fertility ; Follicle Stimulating Hormone ; Humans ; Hypogonadism ; Infertility ; Infertility, Male ; Male ; Oligospermia ; Reference Values ; Reproductive Techniques, Assisted ; Semen ; Spermatozoa ; Testosterone

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

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

Most diabetic patients experience diabetic mellitus (DM) urinary bladder dysfunction. A number of studies evaluate bladder smooth muscle contraction in DM. In this study, we evaluated the change of bladder smooth muscle contraction between normal rats and DM rats. Furthermore, we used pharmacological inhibitors to determine the differences in the signaling pathways between normal and DM rats. Rats in the DM group received an intraperitoneal injection of 65 mg/kg streptozotocin and measured blood glucose level after 14 days to confirm DM. Bladder smooth muscle contraction was induced using acetylcholine (ACh, 10⁻⁴ M). The materials such as, atropine (a muscarinic receptor antagonist), U73122 (a phospholipase C inhibitor), DPCPX (an adenosine A1 receptor antagonist), udenafil (a PDE5 inhibitor), prazosin (an α₁-receptor antagonist), papaverine (a smooth muscle relaxant), verapamil (a calcium channel blocker), and chelerythrine (a protein kinase C inhibitor) were pre-treated in bladder smooth muscle. We found that the DM rats had lower bladder smooth muscle contractility than normal rats. When prazosin, udenafil, verapamil, and U73122 were pre-treated, there were significant differences between normal and DM rats. Taken together, it was concluded that the change of intracellular Ca²⁺ release mediated by PLC/IP3 and PDE5 activity were responsible for decreased bladder smooth muscle contractility in DM rats.
Acetylcholine ; Animals ; Atropine ; Blood Glucose ; Calcium Channels ; Humans ; Injections, Intraperitoneal ; Muscle, Smooth* ; Papaverine ; Prazosin ; Protein Kinase C ; Rats* ; Receptor, Adenosine A1 ; Receptors, Muscarinic ; Streptozocin ; Type C Phospholipases ; Urinary Bladder* ; Verapamil

Bladder dysfunction is a common complication of diabetes mellitus (DM). However, there have been a few studies evaluating bladder smooth muscle contraction in DM in the presence of pharmacological inhibitors. In the present study, we compared the contractility of bladder smooth muscle from normal rats and DM rats. Furthermore, we utilized pharmacological inhibitors to delineate the mechanisms underlying bladder muscle differences between normal and DM rats. DM was established in 14 days after using a single injection of streptozotocin (65 mg/kg, intraperitoneal) in Sprague-Dawley rats. Bladder smooth muscle contraction was induced electrically using electrical field stimulation consisting of pulse trains at an amplitude of 40 V and pulse duration of 1 ms at frequencies of 2–10 Hz. In this study, the pharmacological inhibitors atropine (muscarinic receptor antagonist), U73122 (phospholipase C inhibitor), DPCPX (adenosine A₁ receptor antagonist), udenafil (PDE5 inhibitor), prazosin (α₁-receptor antagonist), verapamil (calcium channel blocker), and chelerythrine (protein kinase C inhibitor) were used to pretreat bladder smooth muscles. It was found that the contractility of bladder smooth muscles from DM rats was lower than that of normal rats. In addition, there were significant differences in percent change of contractility between normal and DM rats following pretreatment with prazosin, udenafil, verapamil, and U73122. In conclusion, we suggest that the decreased bladder muscle contractility in DM rats was a result of perturbations in PLC/IP₃-mediated intracellular Ca²⁺ release and PDE5 activity.
Animals ; Atropine ; Diabetes Mellitus ; Muscle, Smooth ; Phosphotransferases ; Prazosin ; Rats* ; Rats, Sprague-Dawley ; Streptozocin ; Type C Phospholipases ; Urinary Bladder* ; Verapamil