Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; pathology ; Cell Line ; Hep G2 Cells ; Humans ; Lactones ; pharmacology ; Sulfones ; pharmacology

OBJECTIVETo investigate the ultrasonographic indexes in the evaluation of complete penile erection after oral administration of sildenafil citrate in men with normal erectile function.

METHODSThe subjects lay supine, with the penis raised upwards, its back clinging to the abdomen. The probe was placed at the base of the ventral side of the penis for longitudinal and transverse section scanning. Observations were made on the corpus cavernosum, deep artery and deep dorsal vein of the penis at the time of flaccidity and complete erection after oral administration of sildenafil citrate, respectively.

RESULTSThe examinations were acceptable to all the subjects both physically and psychologically, and all were completed successfully with no complications. Compared with the flaccid state of the penis, obvious changes were observed in the state of complete erection, including marked increases in the diameter of the corpus cavernosum ([18.57 +/- 2.50] mm, increased by [106.8 +/- 62.1]%), the inside diameter of the deep artery ([1.18 +/- 0.26] mm, increased by [54.9 +/- 29.0]%), the peak systolic velocity ([32.5 +/- 10.7] cm/s, increased by [209.3 +/- 112.9]%), and the systolic acceleration ([5.71 +/- 2.71] cm/s2, increased by [179.3 +/- 138.2]%).

CONCLUSIONOral administration of sildenafil citrate followed by ultrasonography is a new approach to the objective evaluation of penile erection, characterized by convenience, safety, non-invasiveness, non-complication, easy acceptability and easy clinical application.

Adult ; Humans ; Male ; Penile Erection ; drug effects ; physiology ; Penis ; diagnostic imaging ; Piperazines ; pharmacology ; Purines ; pharmacology ; Sildenafil Citrate ; Sulfones ; pharmacology ; Ultrasonography

The remarkable therapeutic success of PDE5 inhibitors in the treatment of male erectile dysfunction has focused the attention of the researchers on better defining the properties of the individual inhibitors and PDE5 that contribute to the high affinity of these inhibitors for interaction with the PDE5 catalytic site. Recent molecular studies have demonstrated that vardenafil has high affinity for PDE5 and low dissociation rate from PDE5, which serves to explain why vardenafil works with low dosage, onsets quickly and has curative action in clinical practice. Moreover, the potency of vardenafil depends on its ring structure that resembles the purine moiety in cGMP.
Drug Interactions ; Erectile Dysfunction ; drug therapy ; Humans ; Imidazoles ; chemistry ; pharmacology ; Male ; Molecular Structure ; Phosphodiesterase Inhibitors ; chemistry ; pharmacology ; Piperazines ; chemistry ; pharmacology ; Sulfones ; chemistry ; pharmacology ; Triazines ; chemistry ; pharmacology ; Vardenafil Dihydrochloride

OBJECTIVETo evaluate the efficacy of sildenafil on nocturnal penile tumescence (NPT).

METHODSThirty-five patients with erectile dysfunction (ED), 28 cases of organic ED and 7 cases of psychogenic ED, were treated with sildenafil 100 mg before bedtime. The NPT of the patients was observed by using NEVA.

RESULTSErectile function significantly improved in the 28 cases of organic ED (P < 0.05), but not in the 7 cases of psychogenic ED (P > 0.05).

CONCLUSIONSildenafil can improve NPT of organic ED patients without sexual stimulation.

Adult ; Erectile Dysfunction ; drug therapy ; physiopathology ; Humans ; Male ; Middle Aged ; Penile Erection ; drug effects ; Phosphodiesterase Inhibitors ; pharmacology ; Piperazines ; pharmacology ; Purines ; pharmacology ; Sildenafil Citrate ; Sulfones ; pharmacology

OBJECTIVETo investigate the protective effects of sildenafil to noise-induced hearing loss in guinea pigs.

METHODSGuinea pigs were randomly divided into control group, noise exposure group and the sildenafil treatment group, with 10 in each group. One week after the exposure of 110 dB (A) white noise, sildenafil [10 mg/(kg×d)] and normal saline [4 ml/(kg×d)] were injected into guinea pigs of noise plus sildenafil group (NSG) and noise plus normal saline group(NNG) respectively. One week after noise exposure to four weeks continuous administration. ABR thresholds were measured respectively prior to the experiment, 1 week post-noise, 1, 2 and 4 weeks post-drugs. The changes of cochlea hair cells were also observed by scanning electron microscope (SEM).

RESULTSAfter noise exposure, the ABR threshold shifts in NSG were significantly fewer than that in the NNG. An average of 19.1 dB in NNG compared with 19.8 dB in NSG. Four weeks after exposure, the threshold shifts were become larger to 22.0 dB in NNG while become smaller to 4.8 dB in NSG. Compared NNG with NSG, in addition to noise exposure time point, there were statistically significant differences in the rest time points after administration of the ABR threshold (P<0.05). SEM showed that the inner and outer hair cells in NNG displayed mess, fusion and imperfections. In NSG, the hair cells displayed slight pathological changes, there was no significant difference when compared with control group.

CONCLUSIONSildenafil is able to reduce the ascending of ABR thresholds shift, and it can significantly protect against noise-induced hearing loss.

Animals ; Auditory Threshold ; drug effects ; Cochlea ; drug effects ; Guinea Pigs ; Hair Cells, Auditory ; drug effects ; Hearing Loss, Noise-Induced ; physiopathology ; Piperazines ; pharmacology ; Purines ; pharmacology ; Sildenafil Citrate ; Sulfones ; pharmacology

OBJECTIVETo obtain related pharmacodynamic data for the clinical experiment by observing the sexual activities of male rats after using sildenafil ciltrate through stomach irrigation.

METHODSForty male Sprague-Dawley rats were distributed into 4 groups with different dosages (control with distilled water, low dosage: 0.08%, medium dosage: 0.24% and high dosage: 0.72%). After the male Sprague-Dawlay rats were mated with their female counterparts in pairs, the latent period of chasing, the frequencies of chasing in 60 minutes, the latent period of intercourse and the frequencies of intercourse in 60 minutes were recorded.

RESULTSCompared with the control, the frequencies of chasing were significantly increased and the latent periods of chasing were significantly shortened in both high dosage and medium dosage groups after using sildenafil (P < 0.01); The frequencies of intercourse in 60 minutes were significantly increased and the latent periods of intercourse were significantly shortened in all the groups after the use of sildenafil.

CONCLUSIONSThe sexual activities of male rats treated with sildenafil were significantly activated.

Animals ; Dose-Response Relationship, Drug ; Male ; Phosphodiesterase Inhibitors ; pharmacology ; Piperazines ; pharmacology ; Purines ; Rats ; Rats, Sprague-Dawley ; Sexual Behavior, Animal ; drug effects ; Sildenafil Citrate ; Sulfones

AIMTo investigate a possible potentiation effect of apomorphine (APO) on sildenafil-induced penile erection in the conscious rabbit.

METHODSErection of male New Zealand White rabbits (3.5 - 4.0 kg, n=12) was assessed by measuring the length of the uncovered penile mucosa and the duration of erection before and after intravenous administration of agents. After injection of APO (0, 0.05, 0.1 and 0.4 mg/kg), sildenafil was administered intravenously in a dose-response manner (0.5, 1 and 5 mg/kg). In additional experiments, the effect of increasing doses of sildenafil in combination with APO on systemic blood pressure was evaluated.

RESULTSSystemic administration of sildenafil induced a dose-dependent increase in the penile length. Intravenous injection of APO alone did not produce any change in the penile length, while significantly enhanced the penile erection induced by sildenafil. The co-administration of 0.1 mg/kg of APO and 1 mg/kg of sildenafil was found to be the most effective combination in producing penile erection. Intravenous administration of sildenafil caused a concentration-dependent decrease in systemic blood pressure, but no additional decrease was observed with co-administration of APO.

CONCLUSIONAPO enhances the penile erection induced by sildenafil in the conscious rabbit without causing an additional decrease in blood pressure.

Animals ; Apomorphine ; pharmacology ; Blood Pressure ; drug effects ; Consciousness ; Drug Synergism ; Male ; Penile Erection ; drug effects ; physiology ; Piperazines ; pharmacology ; Purines ; Rabbits ; Sildenafil Citrate ; Sulfones

OBJECTIVETo investigate the protective effects of Cariporide on immature rabbit heart, and to search for the protective mechanism of the Na(+)/H(+) exchange inhibitor on immature rabbit hearts.

METHODSNew Zealand immature rabbits were randomly divided into two groups (n = 12 in each group). The isolated rabbit heart model was involved in this study. The hearts were submitted to 60 minutes of normothermic ischemia with cardioplegia per 20 minutes of reperfusion. Group I received St. Thomas No2 as cardioprotective solution. Group II received St. Thomas No2 with addition of cariporide (10 micro mol/L). The left ventricular function was recorded, including left ventricular systolic pressure (LVSP), left ventricular dystolic pressure (LVDP), coronary artery flow (CAF), mean aortic pressure (MAP), aortic flow (AF) and dp/dt max. The levels of creatine phosphokinase (CK), lactic dehydrogenase (LDH) of coronary sinus venous solution were measured. The ventricular cardiomyocytes isolated from other 6 immature rabbit hearts were subdivided into 3 groups of each heart, which were attained by means of collagenase-perfusion. All cells were incubated with calcium fluoresence indicator Fluo-3/AM, and then the intracellular free calcium was measured under the laser scanning con-focal microscopy. The baseline was measured after isolation without anoxic/re-oxygenation. The control group received anoxic conditions for 60 minutes and re-oxygenation for 30 minutes, then was measured. The experiment group received the same conditions as control group with addition of Cariporide (1 micromol/L).

RESULTSAfter ischaemia/reperfusion, the percentage of recovery of myocardial function in group II was much better than group I; the LVDP, LVSP, MAP, AF, CAF and dp/dt max showed markedly better recovery in group II. The release of CK, LDH was significantly increased in Group I. After anoxic/re-oxygenation, the intracellular free calcium of isolated immature rabbit ventricular myocytes in control group increased significantly than baseline (P < 0.01); there were no significant difference of immature myocardial [Ca(2+)]i between experiment group and baseline (P > 0.05); and the experiment group myocardial [Ca(2+)]i reduced significantly than control (P < 0.01).

CONCLUSIONSCariporide demonstrates significant cardio-protective effects for immature myocardium ischemia/reperfusion, and the protective mechanism may be due to the inhibition of the intracellular free calcium overload.

Animals ; Arrhythmias, Cardiac ; etiology ; Calcium ; metabolism ; Female ; Guanidines ; pharmacology ; Male ; Myocardial Reperfusion Injury ; prevention & control ; Rabbits ; Sodium ; metabolism ; Sodium-Hydrogen Exchangers ; antagonists & inhibitors ; Sulfones ; pharmacology

AIMTo examine the effect of sildenafil citrate on penile erection of male rhesus macaque.

METHODSTwenty Macaca mulatta were divided into the sildenafil treated and the control groups of 10 animals each. The penile size, the corpus cavernosal electromyogram (EMG) and the intra-corpus cavernosal pressure (ICP) were determined.

RESULTSThe diameter of penis and the ICP were significantly increased and the corpus cavernosal EMG significantly reduced in the sildenafil group.

CONCLUSIONSildenafil citrate increases the penile size and ICP and reduces the corpus cavernosal EMG in male rhesus macaque.

Animals ; Electromyography ; Macaca mulatta ; Male ; Penile Erection ; drug effects ; physiology ; Penis ; anatomy & histology ; drug effects ; Piperazines ; pharmacology ; Purines ; Sildenafil Citrate ; Sulfones ; Vasodilator Agents ; pharmacology

OBJECTIVETo explore the effect of ataxia telangiectasia mutated and RAD3 related protein (ATR) expression and ATR kinase activity on the sensitivity to cisplatin in ovarian cancer SKOV3 cells.

METHODSSiRNA targeting ATR was transfected into SKOV3 cells for 48 h to reduce the ATR protein level, and ATR kinase inhibitor VE-821 was used for 12 h to inhibit the ATR pathway activity. The alteration of cell viability was examined by CCk-8 assay. Expression levels of ATR, p-ATR and γ-H2AX proteins were detected by Western blot. The DNA double strand breaks (DSB) marker γ-H2AX and homologous recombination repair key protein RAD51 and their co-localization in the cells were examined under the confocal microscope. The status of DNA double strand breaks (DSB) in single cells was visualized by alkaline comet assay. Finally, the cell cycle distribution was assessed using flow cytometry.

RESULTSDDP caused evident DNA double strands breaks and activated ATR kinase pathway. ATR-siRNA notably reduced ATR protein level, the 48 h IC(50) value of DDP was 72.12 µmol/L and 41.25 µmol/L, respectively, in the NC-siRNA and ATR-siRNA groups (P < 0.05). Confocal microscopic assay presented decreased recruitment of RAD51 at the DSB loci and comet assay showed enhanced DSB in the cells after ATR knocking down. After the inhibition of ATR kinase by VE-821, the 48 h IC(50) value of DDP was 75.32 µmol/L and 45.64 µmol/L, respectively, in the DMSO and VE-821 groups (P < 0.05 for both), confocal microscopic assay demonstrated reduced RAD51 recruitment, and comet assay showed increased DSB in cells after ATR kinase inhibition. Flow cytometry showed that percentage of cells distributed in G(0)/G(1), S and G(2)/M phases was 71.2%, 13.4% and 15.4%, repectively, after 40 µmol/L DDP treatment for 24 h. Compared with that of control group (G(0)/G(1): 54.2%, S: 21.3% and G(2)/M: 24.4%), DDP induced G(0)/G(1) phase arrest. DDP intervention resulted in the cell cycle status (G(0)/G(1): 43.2%, S: 20.4%, G(2)/M: 36.4%) in the ATR-siRNA group and (G(0)/G(1): 40.2%, S: 22.5%, G(2)/M: 37.3%) in the VE-821 group, indicating that the inhibition of ATR or ATR kinase could abrogate the effect of G(0)/G(1) phase arrest induced by DDP.

CONCLUSIONSSuppression of ATR can affect the homologous recombination repair in ovarian cancer cells, leading to accumulation of DNA double strand breaks in the cell nuclei as well as reduction of DDP-caused G(0)/G(1) phase arrest, finally enhances the sensitivity to cisplatin in the ovarian cancer SKOV3 cells.

Antineoplastic Agents ; pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cisplatin ; pharmacology ; DNA Repair ; Female ; Humans ; Ovarian Neoplasms ; Pyrazines ; RNA, Small Interfering ; Sulfones ; Transfection