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Sildenafil
Kinds of Sildenafil Terms modified by Sildenafil Selected AbstractsFK506 and Sildenafil Promote Erectile Function Recovery after Cavernous Nerve Injury Through Antioxidative MechanismsTHE JOURNAL OF SEXUAL MEDICINE, Issue 4i 2007Gwen Lagoda MS ABSTRACT Introduction., Immunophilin ligands and phosphodiesterase type 5 (PDE5) inhibitors are touted to promote erectile function recovery after cavernous nerve (CN) injury. However, the mechanisms for their effects remain unclear. Aim., To compare the erection recovery effects of the immunophilin ligand FK506 and the PDE5 inhibitor sildenafil after CN injury and determine whether they involve antioxidative and/or antiapoptotic mechanisms. Methods., Initial experiments established conditions of our CN injury model in adult male Sprague-Dawley rats. Subsequently, we evaluated treatment effects 14 days after: (i) unilateral CN injury (UNI) + saline (vehicle control); (ii) UNI + FK506 (5 mg/kg once daily, subcutaneous ×5 days); (iii) UNI + sildenafil (20 mg/kg every 8 hours, subcutaneous ×7 days); (iv) UNI + FK506/sildenafil; and (v) sham surgery. Main Outcome Measures., Intracavernous pressure (ICP) measurement after CN electrical stimulation to assess erectile function and Western blot analysis of expressions of glutathione peroxidase (GPX; antioxidant enzyme), nitrotyrosine (NT; oxidative stress marker), and phosphorylated and total Akt (antiapoptotic factor) in penes. Results., In the UNI model, GPX expression was increased at Days 1 and 7, while p-Akt expression decreased at Day 1 and returned to baseline at Day 7. GPX expression was significantly higher in the UNI + FK506 group compared with the saline-treated group (P < 0.05). ICP increased in all treatment groups compared with that of the saline-treated group (P < 0.05). NT levels were increased after saline treatment (P < 0.05) but not after FK506 and sildenafil treatment, alone or in combination. GPX was localized to nerves coursing through the penis and to smooth muscle and endothelium of the dorsal vein and arteries. Conclusions., Both FK506 and sildenafil protect erectile function after CN injury by decreasing oxidative stress-associated tissue damage. FK506 may act through increased GPX activity. Further research is required to elucidate mechanisms associated with the beneficial effect of sildenafil. Lagoda G, Jin L, Lehrfeld TJ, Liu T, and Burnett AL. FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms. J Sex Med 2007;4:908,916. [source] A FATAL HYPOTENSION BY SILDENAFIL IN AN END-STAGE RENAL DISEASE PATIENT WITH HYPERTENSION AND ABNORMAL PHARMACOKINETICS OF THE MEDICINENEPHROLOGY, Issue 3 2009YOSHIHIRO WADA [source] EFFECT OF THE PHOSPHODIESTERASE 5 INHIBITORS SILDENAFIL, TADALAFIL AND VARDENAFIL ON RAT ANOCOCCYGEUS MUSCLE: FUNCTIONAL AND BIOCHEMICAL ASPECTSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2009Haroldo A Toque SUMMARY 1The anococcygeus muscle is part of the erectile machinery in male rodents. Phosphodiesterase (PDE) 5 inhibitors enhance and prolong the effects of cGMP, which has a key role in penile erection. The aim of the present study was to provide a functional and biochemical comparison of the three PDE5 inhibitors, namely sildenafil, tadalafil and vardenafil, in the rat anococcygeus muscle. 2Muscle strips were mounted in 4 mL organ baths and isometric force recorded. Levels of cGMP were measured using an enzyme immunoassay kit. Western blots were used to determine PDE5 protein expression. 3The PDE5 inhibitors concentration-dependently relaxed carbachol-precontracted anococcygeus muscle; however, vardenafil was more potent (pEC50 = 8.11 ± 0.05) than sildenafil (7.72 ± 0.06) or tadalafil (7.69 ± 0.05). Addition of NG -nitro- l -arginine methyl ester (100 µmol/L) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 µmol/L) to the organ baths caused significant rightward shifts in concentration,response curves for all PDE5 inhibitors. 4Sildenafil, tadalafil and vardenafil (all at 0.1 µmol/L) caused leftward shifts in the glyceryl trinitrate (GTN) concentration-response curves (by 4.0-, 3.7- and 5.5-fold, respectively). In addition, all three PDE5 inhibitors significantly potentiated relaxation responses to both GTN (0.01,10 µmol/L) and electrical field stimulation (EFS; 1,32 Hz), with vardenafil having more pronounced effects. 5All three PDE5 inhibitors reduced EFS-evoked contractions in a concentration-dependent manner over the concentration range 0.001,1 µmol/L. There were no significant differences between the effects of the three PDE5 inhibitors. 6Vardenafil (0.01,0.1 µmol/L) was more potent in preventing cGMP degradation in vitro than sildenafil (0.01,0.1 µmol/L) and tadalafil (0.01,0.1 µmol/L). 7Under control conditions, the expression of PDE5 was higher in the anococcygeus muscle than in the corpus cavernosum. 8In conclusion, PDE5 inhibitors enhance exogenous and endogenous nitric oxide-mediated relaxation in the rat anococcygeus muscle. The potency of vardenafil was greater than that of either sildenafil or tadalafil. [source] Potential Role of Type 5 Phosphodiesterase Inhibition in the Treatment of Congestive Heart FailureCONGESTIVE HEART FAILURE, Issue 1 2003Stuart D. Katz MD Endothelial dysfunction is associated with impairment of aerobic capacity in patients with heart failure and may play a role in the progression of disease. Impaired endothelium-dependent vasodilation in patients with heart failure can be attributed to decreased bioavailability of nitric oxide and attenuated responses to nitric oxide in vascular smooth muscle. Impaired vasodilation in response to nitric oxide derived from vascular endothelium or organic nitrates in vascular smooth muscle may be related in part to increased degradation of the second messenger cyclic guanosine monophosphate by type 5 phosphodiesterase. Sildenafil, a specific type 5 phosphodiesterase inhibitor currently approved for the treatment of erectile dysfunction, has been shown to acutely enhance endothelium-dependent vasodilation in patients with heart failure. Further studies are warranted to characterize the safety and efficacy of type 5 phosphodiesterase inhibition in the treatment of chronic heart failure. [source] Sildenafil Can Trigger Cluster HeadachesHEADACHE, Issue 1 2006Randolph W. Evans MD Phosphodiesterase-5 inhibitors commonly trigger migraines but rarely trigger cluster headaches. Two cases of cluster headaches triggered by sildenafil are described. [source] Can sildenafil treat primary premature ejaculation?INTERNATIONAL JOURNAL OF UROLOGY, Issue 4 2007A prospective clinical study Background: Recently, sildenafil has been demonstrated to be effective in treating premature ejaculation (PE). However, these studies ignored female factors and could not exclude the probability of drug interaction when combined with paroxetine. Therefore, the aim of this study was to evaluate the efficacy and safety of sildenafil alone in the treatment of primary PE, taking female factors into consideration. Methods: One hundred and eighty potent men with primary PE were randomly divided into three groups and followed up for 6 months. Group A were treated with 50 mg sildenafil as needed, group B with 20 mg paroxetine daily and group C with squeeze technique daily. Intravaginal ejaculatory latency time (IELT), PE grade, intercourse satisfactory score (ISS), frequency of intercourse, and adverse effects of drugs were recorded before treatment, and 3 and 6 months after treatment. Results: Compared with pretreatment, the three groups had significant differences in all the parameters after 3 or 6 months treatment, except the frequency of intercourse in Group C (all P = 0.00). However, there were no significant differences between 3 and 6 months. Compared with paroxetine and squeeze technique, after 3 or 6 months, sildenafil had significant differences in all the parameters (all P = 0.00). After 6 months, 1.7%, 18.3% and 36.7% patients in groups A, B and C, respectively, withdrew from the study and 86.7%, 60.0% and 45.0% patients, respectively, wanted to be treated further with the original administration, and this was statistically significant (both P = 0.00). Conclusion: Sildenafil is very effective and safe to treat PE, and has much higher efficacy than paroxetine and squeeze technique. [source] The effect of sildenafil, a phosphodiesterase-5 inhibitor, on acetic acid-induced colonic inflammation in the ratJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 6 2009Sevgin Ozlem Iseri Abstract Background and Aim:, Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. Methods:, Colitis was induced by intrarectal administration of 1 mL of 5% acetic acid to Sprague-Dawley rats (200,250 g; n = 7,8/group). Control rats received an equal volume of saline intrarectally. In treatment groups, the rats were treated with either sildenafil citrate (5 mg/kg/day; subcutaneously) or saline for 3 days. After decapitation, distal colon was weighed and scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and oxidant production. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-, and interleukin (IL)-1, levels. Results:, In the colitis group, the colonic tissue was characterized by lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and oxidant production. Serum TNF-, and IL-1, levels were higher in the colitis group compared to control values. Sildenafil reversed these inflammatory parameters nearly back to control values. Conclusions:, Sildenafil citrate administration to rats with acetic acid-induced colitis seems to be beneficial via prevention of lipid peroxidation, oxidant generation, cytokine production and neutrophil accumulation. [source] Retrospective Evaluation of Sildenafil Citrate as a Therapy for Pulmonary Hypertension in DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2006Jonathan F. Bach DACVIM (SA-IM) Pulmonary arterial hypertension (PH) is a pathologic condition in dogs characterized by abnormally high pressures in the pulmonary circulation and has been associated with a poor outcome. Sildenafil is a type V phosphodiesterase inhibitor that produces nitric oxide-mediated vasodilatation. Sildenafil treatment decreases pulmonary arterial pressure and pulmonary vascular resistance in people with PH. The purpose of this study was to describe the clinical characteristics and outcome of dogs with PH treated with sildenafil. The cardiology database was searched for dogs with PH treated with sildenafil. PH was defined as systolic pulmonary arterial pressure (PAPS) 25 mmHg at rest. Medical records were reviewed for the following information: signalment, duration and type of clinical signs before treatment, underlying disease, estimated or measured PAPS, dosage and dosing interval of sildenafil, and the effect of treatment on clinical signs and pulmonary arterial pressure and survival time. Thirteen affected dogs were identified. Clinical signs included collapse, syncope, respiratory distress, and cough. Duration of clinical signs before presentation ranged from 3 days to 5 months. An underlying cause was identified in 8 dogs. The median sildenafil dosage was 1.9 mg/kg. Ten dogs received concurrent medications. Median PAPS was 90 mmHg; 8 dogs were reevaluated after therapy, and the median decrease in PAPS was 16.5 mmHg. The median survival time of all dogs was 91 days. Sildenafil appeared to be well tolerated in dogs with PH and was associated with decreased PAPS and amelioration of clinical signs in most. Sildenafil represents a reasonable treatment option for dogs with pulmonary hypertension. [source] Systemic and splanchnic haemodynamic effects of sildenafil in an in vivo animal model of cirrhosis support for a risk in cirrhotic patientsLIVER INTERNATIONAL, Issue 1 2004Isabelle Colle Abstract: Objectives: Sildenafil is a selective inhibitor of the cGMP-specific phosphodiesterase type V (PDE-V) in the corpus cavernosum. PDE-V is also present in the mesenteric artery. Cirrhosis is complicated by a splanchnic vasodilation attributed to a local overproduction of nitric oxide (NO). As sildenafil potentiates the effects of NO, it may further decrease mesenteric vascular tone and increase portal venous blood flow. The aim is to evaluate the effects of sildenafil on the systemic and splanchnic haemodynamics in an experimental model of cirrhosis. Methods: Secondary biliary cirrhosis was induced in male Wistar rats by common bile duct ligation (CBDL, n=8); control rats were sham-operated (sham, n=7). The mean arterial pressure (MAP), portal venous pressure (PVP) and arterial mesenteric blood flow (MBF) were measured after intramesenteric (0.01,10 mg/kg) and after intravenous (i.v.) (0.01,10 mg/kg) administration of sildenafil. Results: Baseline PVP was significantly higher in CBDL than in sham rats, whereas baseline MAP tended to be lower and MBF tended to be higher in CBDL compared with sham rats. Both intramesenteric and i.v. injection of sildenafil significantly decreased MAP and increased MBF and PVP in a dose-dependent way. The decrease in MAP was significantly less important in CBDL than in sham rats. The increase in MBF was importantly lower in CBDL than in sham rats. PVP tended to increase more significantly in sham rats than in CBDL. Conclusion: Sildenafil increases MBF and PVP and induces systemic hypotension. The effects are less pronounced in cirrhosis, suggesting vascular hyporesponsiveness to sildenafil. Although the rise in PVP in cirrhotic animals is smaller than in controls, it may present a risk for haemorrhagic complications. Further studies are necessary before prescribing sildenafil to patients with cirrhosis. [source] Expression and function of phosphodiesterases in nitrofen-induced congenital diaphragmatic hernia in ratsPEDIATRIC PULMONOLOGY, Issue 4 2010Irene W.J.M. van der Horst MD Abstract Background Congenital diaphragmatic hernia (CDH) is an anomaly associated with pulmonary hypoplasia and pulmonary hypertension (PH). The limited efficacy of current approaches to treat PH in CDH, including inhaled nitric oxide (NO), drives the search for other therapies. Phosphodiesterases (PDEs) degrade cyclic nucleotide second messenger cAMP and cGMP downstream of NO thereby limiting the vasodilatory response to NO. Objective To identify therapeutic targets by cataloguing the expression and function of PDE isoforms in the pulmonary vasculature in nitrofen-induced CDH in fetal rats. Methods/Results Quantitative RT-PCR revealed PDE1,5 and PDE9 mRNA expression in pulmonary arteries (PAs) of control and nitrofen-induced CDH term fetal rats. In this order of potency, the PDE inhibitors Sildenafil (PDE5),>,EHNA (PDE2),>,Rolipram (PDE4),>,Cilostamide (PDE3) all dilated isolated third generation PA after pre-constriction with the thromboxane analog U46619. Hyperoxic pre-incubation of PAs significantly attenuated vasodilatation induced by the PDE5 inhibitor Sildenafil (65% vs. 33%, P,<,0.004). CDH PAs dilated significantly less to PDE2 inhibitor EHNA compared to control (51% vs. 72%, P,<,0.05). Subsequently PDE2 protein expression was higher in PAs of CDH animals. Conclusion Most PDE isoforms exist in the PAs of fetal rats and their inhibition causes pulmonary vasodilatation. PDE5 inhibition was the most potent vasodilator, however, there were no differences between groups. PDE5-induced vasodilatation was attenuated by hyperoxic pre-incubation. PDE inhibitors might be considered therapeutic targets in combination with iNO in neonates with CDH. Pediatr Pulmonol. 2010; 45:320,325. © 2010 Wiley-Liss, Inc. [source] A gas chromatography/mass spectrometry method for the determination of sildenafil, vardenafil and tadalafil and their metabolites in human urineRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 11 2010Sabina Strano-Rossi Sildenafil (SDF), vardenafil (VDF) and tadalafil (TDF) are phosphodiesterase type 5 enzyme inhibitors (PDE5Is), used in the treatment of erectile disorders and to improve breathing efficiency in pulmonary hypertension. The increasing incidence of their use among young athletes has drawn the attention of the anti-doping authorities to the possible abuse of PDE5Is by athletes due to their pharmacological activities. This paper describes a method for the determination in urine of PDE5Is and their metabolites by gas chromatography/mass spectrometry (GC/MS) after liquid/liquid extraction of the analytes from urine and derivatisation to obtain trimethylsilyl derivatives. The metabolic profile was studied on real samples collected from subjects taking PDE5Is (Viagra®, Levitra® or Cialis®); the main urinary metabolites were identified and their MS fragmentation characterized. The sample pre-treatment and GC/MS conditions for the detection of the metabolites have been optimised. A method for their preliminary screening and subsequent confirmation is described that takes into account the general requirements of a routine doping analysis to be used for the screening of large numbers of samples. The main metabolites identified can be included in a general purpose screening method and all the metabolites in a more specific confirmation method. The method developed has been applied for the screening of PDE5Is in 5000 urine samples. Based on the obtained results, the proposed method appears to be of practical use in analytical and forensic toxicology, including doping analysis. Copyright © 2010 John Wiley & Sons, Ltd. [source] First Successful Pregnancy after Addition of Enoxaparin to Sildenafil and Etanercept Immunotherapy in Woman with Fifteen Failed IVF Cycles , Case ReportAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2010gorzata Jerzak Citation Jerzak M, Niemiec T, Nowakowska A, Klochowicz M, Górski A, Baranowski W. First successful pregnancy after addition of enoxaparin to sildenafil and etanercept immunotherapy in woman with fifteen failed in vitro fertilization (IVF) cycles , case report. Am J Reprod Immunol 2010; 64: 93,96 Problem, Does addition of enoxaparin to sildenafil and etanercept immunotherapy improve IVF outcome? Methods, Report of a striking case with 15 IVF failures. Result, When enoxaparin was added, the 16th IVF cycle generated a healthy male baby. Conclusions, Combination therapy that includes a heparin may allow successful IVF outcome and this issue merits further study. [source] ORIGINAL RESEARCH,ED PHARMACOTHERAPY: Sildenafil Citrate 100 mg Starting Dose in Men with Erectile Dysfunction in an International, Double-Blind, Placebo-Controlled Study: Effect on the Sexual Experience and Reducing Feelings of Anxiety About the Next Intercourse AttemptTHE JOURNAL OF SEXUAL MEDICINE, Issue 10 2009Oleg B. Loran MD ABSTRACT Introduction., Sildenafil citrate 50 mg is the recommended starting dose for men with erectile dysfunction (ED); however, most men are later titrated to sildenafil 100 mg for improved efficacy. Aim., Assess the tolerability and efficacy of sildenafil initiated at the 100-mg dose in men with ED. Methods., Men with ED (score ,25 on the Erectile Function domain of the International Index of Erectile Function) who had received ,6 total doses of a phosphodiesterase type 5 inhibitor and none within 4 weeks were randomized to 8 weeks of double-blind, placebo-controlled (DBPC), fixed-dose treatment (50 or 100 mg sildenafil or placebo) followed by 4 weeks of open-label flexible-dose sildenafil (50 or 100 mg). Main Outcome Measures., Efficacy, tolerability, treatment satisfaction, and other end points were measured at baseline and/or the end of the double-blind and open-label phases and compared between placebo and sildenafil initiated at doses of 50 and 100 mg. Results., Improvements in DBPC patient-reported outcomes from baseline were statistically significant for both sildenafil 50 and 100 mg compared with placebo. At the end of DBPC treatment, 56% of men on the 100-mg dose felt no anxiety about the next intercourse attempt compared with 39% in the 50-mg group (odds ratio 2.03; P = 0.0197). Changes in functional scores from baseline were not statistically significant with the 100-mg dose compared with the 50-mg dose in the DBPC. Measures of treatment satisfaction and sexual experience significantly favored the 100-mg dose compared with the 50-mg dose in the DBPC. There was no increase in adverse events with the higher dose. Conclusions., Sildenafil at 50 mg or 100 mg significantly improved erection quality, treatment satisfaction, anxiety levels, and the sexual experience compared with placebo during DBPC. Sildenafil 100 mg improved the sexual experience and treatment satisfaction, and reduced feelings of anxiety compared with the 50-mg dose. Loran OB, Ströberg P, Lee SW, Park NC, Kim SW, Tseng LJ, Collins S, and Stecher VJ. Sildenafil citrate 100 mg starting dose in men with erectile dysfunction in an international, double-blind, placebo-controlled study: Effect on the sexual experience and reducing feelings of anxiety about the next intercourse attempt. J Sex Med 2009;6:2826,2835. [source] Negative Impact of Metabolic Syndrome on the Responsiveness to Sildenafil in Japanese MenTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2008Takahiro Suetomi MD ABSTRACT Introduction., Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS). Aim., We analyzed the impact of MS on the responsiveness to sildenafil. Methods., A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil. Main Outcome Measures., To clarify the negative impact of MS on the responsiveness to sildenafil. Results., The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17,9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population. Conclusion., We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased. Suetomi T, Kawai K, Hinotsu S, Joraku A, Oikawa T, Sekido N, Miyanaga N, Shimazui T, and Akaza H. Negative impact of metabolic syndrome on the responsiveness to sildenafil in Japanese men. J Sex Med 2008;5:1443,1450. [source] Alternate-Day Tadalafil in the Management of Honeymoon ImpotenceTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2008Hussein Ghanem MD ABSTRACT Introduction., Sildenafil has been used successfully in the treatment of honeymoon impotence. However, no study investigated the potential effect of tadalafil in the treatment of honeymoon impotence. Aim., The aim of this study is to evaluate the effectiveness of alternate-day tadalafil therapy in the management of unconsummated marriages. Methods., This is a descriptive study comprised of a series of 45 patients. The time frame for the study was 2 years. Forty-five consecutive patients underwent a complete medical and sexual history as well as a focused physical examination. Education about the male and female genital anatomy and the sexual response cycle was carried out. Alternate-day tadalafil 10-mg therapy was administered for 2 weeks with the duration extended as needed. Main Outcome Measures., Primary efficacy endpoints were successful vaginal intromission and change in the abridged version of the International Index of Erectile Function (IIEF-5). Results., Of 45 patients included in our study, 41 (91%) were able to achieve vaginal intromission and perform sexually. Thirty-four patients (76%) needed tadalafil for less than 1 month, five (11%) for up to 3 months, and two (4%) for more than 3 months. Four patients (9%) were unsuccessful. IIEF-5 improved significantly with alternate-day tadalafil treatment in this subgroup of patients (P < 0.001). Treatment failures were managed by intracavernous injection therapy, combined with psychosexual therapy, depending on the cause. Conclusions., Tadalafil therapy was safe and effective in the short-term management of this selected group of honeymoon impotence patients. Controlled studies are needed to further confirm these findings. Ghanem H, El-Dakhly M, and Shamloul R. Alternate-day tadalafil in the management of honeymoon impotence. J Sex Med 2008;5:1451,1454. [source] Investigating Women's Preference for Sildenafil or Tadalafil Use by Their Partners with Erectile Dysfunction: The Partners' Preference StudyTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2008Helen M. Conaglen PhD ABSTRACT Introduction., Several preference studies comparing a short-acting with a longer-acting phosphodiesterase type 5 inhibitor have been conducted in men. Most men in those studies preferred tadalafil rather than sildenafil, and recent post hoc analysis of one study described several factors associated with men's treatment preference. No prospective studies have investigated the woman partners' preferences. Aim., To investigate the treatment preference of women who were partners of men using oral medications for erectile dysfunction (ED) in a single-center open-label crossover study. Methods., One hundred heterosexual couples in stable relationships, with male partners having ED based on the erectile function subscale of the International Index of Erectile Function, were randomly assigned to receive sildenafil or tadalafil for a 12-week phase, followed by another 12-week period using the alternate drug. Male and female participants completed sexual event diaries during both study phases, and the female participants were interviewed at baseline, midpoint, and end of study. Main Outcome Measures., Primary outcome data were the women's final interviews during which they were asked which drug they preferred and their reasons for that preference. Results., A total of 79.2% of the women preferred their partners' use of tadalafil, while 15.6% preferred sildenafil. Preference was not affected by age or treatment order randomization. Women preferring tadalafil reported feeling more relaxed, experiencing less pressure, and enjoying a more natural or spontaneous sexual experience as reasons for their choice. Mean number of tablets used, events recorded, events per week, and days between events were not significantly different during each study phase. Conclusion., Women's preferences were similar to men when using these two drugs. While the women's reasons for preferring tadalafil emphasized relaxed, satisfying, longer-lasting sexual experiences, those preferring sildenafil focused on satisfaction and drug effectiveness for their partner. Conaglen HM, and Conaglen JV. Investigating women's preference for sildenafil or tadalafil use by their partners with erectile dysfunction: The partners' preference study. J Sex Med 2008;5:1198,1207. [source] Treatment Satisfaction with Sildenafil in a Canadian Real-Life Setting.THE JOURNAL OF SEXUAL MEDICINE, Issue 5 2007A 6-Month Prospective Observational Study of Primary Care Practices ABSTRACT Introduction., While the efficacy of sildenafil for the management of erectile dysfunction (ED) has been demonstrated in randomized clinical trials, few data exist on its effectiveness in a real-life setting. Aim., The objective of this study was to examine the treatment satisfaction and effectiveness with sildenafil in a real-life setting in Canada. Methods., A multicenter, prospective study, using an educational program aimed at optimizing sildenafil treatment, was conducted at 231 primary care sites across Canada. Patients who received their first prescription of sildenafil for ED within the usual practice of medicine were invited to participate in the study. Data were collected through patient self-administered questionnaires. Main Outcome Measures., The Sexual Health Inventory for Men (SHIM) questionnaire was used to determine the erectile function at baseline, month 3 and month 6. Treatment satisfaction at months 3 and 6 was assessed using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire. Results., The intent-to-treat population consisted of 2,573 patients. The mean age was 55 years (18 to 92 years). At baseline, the mean SHIM score was 11.9 with 21.7% of men having severe ED, 22.9% moderate ED, 36.5% mild-to-moderate ED, and 16.9% mild ED. At month 3, the mean SHIM score improved significantly to 18.0 (P < 0.0001) and 33.3% of patients had a SHIM score above 21 (no ED). At 6 months, the mean SHIM score was 18.7. At both months 3 and 6, approximately 89% of patients were satisfied with their treatment (i.e., EDITS score , 50), suggesting no attenuation of the satisfaction over the 6 months of use. Conclusions., The effectiveness of sildenafil in the management of ED was demonstrated in a large cohort of men treated in a primary care setting in this Canadian real-life study. Persistence with therapy and lack of attenuation over time among the vast majority of men was shown. Carrier S, Brock G, Casey R, Tarride J-E, Elliott S, Dugré H, Rousseau C, D'Angelo P, and Defoy I. Treatment satisfaction with sildenafil in a Canadian real-life setting. A 6-month prospective observational study of primary care practices. J Sex Med 2007;4:1414,1421. [source] ORIGINAL RESEARCH,PHARMACOTHERAPY: Hemodynamic Effects of Sildenafil Citrate and Isosorbide Mononitrate in Men with Coronary Artery Disease and Erectile DysfunctionTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2005Graham Jackson ABSTRACT Introduction., Mild hemodynamic effects have been reported with sildenafil citrate therapy. Aim., To compare the hemodynamic effects of sildenafil and isosorbide mononitrate (ISMN) in men with coronary artery disease and erectile dysfunction. Methods., A total of 31 men aged 35 years or older with coronary artery disease (at least 50% narrowing of the left main stem or at least 70% narrowing of any other coronary artery) and erectile dysfunction (receiving medication for erectile dysfunction or scoring less than 26 out of a maximum score of 30 on the erectile function domain questions of International Index of Erectile Function) were randomized to sildenafil 100 mg (n = 10), ISMN 40 mg (n = 11), or placebo (n = 10) in this single-dose multicenter study. Main Outcome Measures., Hemodynamic parameters were measured at baseline, 1, 2, 4, and 6 hours post dose. Results., Compared with baseline, cardiac index increased slightly with sildenafil (0.29 L/min/m2 at 1 hour) and decreased slightly with placebo (,0.12 L/min/m2 at 4 hours) and ISMN (,0.14 L/min/m2 at 1 hour). The stroke volume index increased from baseline at each time point post dose with sildenafil (4.4 mL/m2 at 2 hours), but decreased with ISMN (,5.8 mL/m2 at 1 hour) and placebo (,2.8 mL/m2 at 4 hours). ISMN reduced mean arterial pressure more than sildenafil did (,22 vs. ,10 mm Hg at 2 hours, respectively). Both sildenafil and ISMN increased heart rate (4 vs. 7 beats/minute at 1 hour, respectively) and decreased systemic vascular resistance, but sildenafil produced greater reductions in pulmonary vascular resistance. There were no serious adverse events in the sildenafil group. Conclusions., Sildenafil 100 mg was well tolerated and induced smaller changes in central and peripheral hemodynamic pressures compared with ISMN 40 mg. Moreover, sildenafil selectively reduced pulmonary resistance, which may have clinical importance in pulmonary hypertension. [source] Efficacy of sildenafil on erectile dysfunction of newly-wedsANDROLOGIA, Issue 6 2009Q. He Summary To explore the efficacy of sildenafil on erectile dysfunction (ED) of newly-weds, the author studied 60 outpatients within a month of marriage, who suffered from sexual intercourse (SI) failure caused by ED and showed no improvement after receiving sex education and psychological consultation. The patients were given oral sildenafil, 100 mg for the first and second times, 50 mg for the third and fourth times, no more than once every day, with a 1- to 3-day break between every two times. Four times of sildenafil administration formed one course of treatment. Sildenafil was taken 1 h before SI and was aided with adequate sexual stimulation. The rates of successful SI due to improved erection during and after a course of sildenafil treatment were 93.3% (56/60) and 85% (51/60), both P > 0.05. In the groups with one and more than one SI failure the successful SI rates after a sildenafil treatment course were 93.1% (27/29) and 77.4% (24/31), both P > 0.05. Oral sildenafil with psychological therapy in the treatment of ED of newly-weds proves to be effective in restoring the patients' sexual function and relieving their mental pressure or stress. [source] Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction.ANDROLOGIA, Issue 3 2004A comparative crossover study Summary. To compare the efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction (ED), 40 men were studied. Post-injection penile peak systolic velocity was greater than 25 cm s,1. Twenty men started on apomorphine 2 mg and 20 on sildenafil 50 mg, the doses titrated up to 3 and 100 mg, respectively, if necessary. After a 1-week washout period each group switched to the other treatment mode. Efficacy was the percentage of attempts resulting in erections firm enough for intercourse, based on an event log data. The majority (85%) of the men had concomitant diseases, risk factors for ED and 95% were heavy smokers. The overall success rate of apomorphine was 62.7%, compared with 73.1% of sildenafil (Yates-corrected chi-square, P < 0.0004). The response to apomorphine 2 mg and sildenafil 50 mg was age related. Sildenafil was statistically more effective than apomorphine in impotent men with normal penile Doppler. Given the contraindication of sildenafil in men taking nitrates and the quick time of action of apomorphine, the two drugs are satisfactory first line therapeutic tools in such individuals and the choice should be based on patient's needs and preferences. [source] Sildenafil Improves the Beneficial Haemodynamic Effects of Intravenous Nitrite Infusion during Acute Pulmonary EmbolismBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2008Carlos A. Dias-Junior While previous studies have shown that sildenafil (an inhibitor of cGMP-specific phosphodiesterase type 5) or nitrite (a storage molecule for nitric oxide) produces beneficial effects during acute pulmonary embolism, no previous study has examined whether the combination of these drugs can produce additive effects. Here, we expand previous findings and examine whether sildenafil enhances the beneficial haemodynamic effects produced by a low-dose infusion of nitrite in a dog model of acute pulmonary embolism. Haemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with saline (n = 4), and in embolized dogs (intravenous injections of microspheres) that received nitrite (6.75 µmol/kg intravenously over 15 min. followed by 0.28 µmol/kg/min.) and sildenafil (0.25 mg/kg over 30 min.; n = 8), or nitrite followed by saline (n = 8), or saline followed by sildenafil (n = 7), or only saline (n = 8). Plasma thiobarbituric acid-reactive substances (TBARS) concentrations were determined using a fluorometric method. Acute pulmonary embolism increased pulmonary artery pressure by ,24 mmHg. While the infusion of nitrite or sildenafil infusions reversed this increase by ,42% (both P < 0.05), the combined infusion of both drugs reversed this increase by ,58% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance index. Nitrite or sildenafil alone produced no significant hypotension. However, the combined infusion of both drugs caused transient hypotension (P < 0.05). Both dugs, either alone or combined, blunted the increase in TBARS concentrations caused by acute pulmonary embolism (all P < 0.05). These results suggest that sildenafil improves the beneficial haemodynamic effects of nitrite during acute pulmonary embolism. [source] Simultaneous assay of sildenafil and desmethylsildenafil in neonatal plasma by ultra-performance liquid chromatography,tandem mass spectrometryBIOMEDICAL CHROMATOGRAPHY, Issue 2 2010Bregje C. Witjes Abstract Sildenafil is used to treat pulmonary hypertension in neonatal and pediatric patients. Pharmacokinetic studies in these patients are complicated by the limited sample volume. We present the validation results of an assay method to quantitate sildenafil and desmethylsildenafil simultaneously in 50,µL of plasma. Deuterated sildenafil was used as an internal standard. After liquid,liquid extraction, analytes were separated on an ultra-performance liquid chromatography (UPLC)-column and quantified via tandem mass spectrometry. The calibration range was linear, with acceptable accuracy and a precision of <15% for both compounds. The lower limits of quantification were 1,ng/mL. Matrix effects were present, but inter-plasma batch variability was under 12%. The method was successfully applied to samples from a pharmacokinetic study into sildenafil pharmacokinetics in neonates, making maximum use of the limited number and amount of plasma samples available. Copyright © 2009 John Wiley & Sons, Ltd. [source] Chronic inhibition of nitric-oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafilBJU INTERNATIONAL, Issue 1 2010Serap Gur Study Type , Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)-nitro- l -arginine methyl ester (L-NAME)-induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)-5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L-NAME induces NO-deficient HT. MATERIALS AND METHODS Thirty-six adult Sprague-Dawley male rats were divided into three groups, i.e. a control, L-NAME-HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil-treated L-NAME-HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L-NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ-bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme-linked immunosorbent assay. RESULTS The erectile response was diminished in the HT group. Nitrergic and endothelium-dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L-NAME-treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels. CONCLUSIONS Sildenafil treatment did not correct the ED in L-NAME-treated HT rats. Under sustained high blood pressure, up-regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium-dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT. [source] Safety and efficacy of sildenafil citrate in treating erectile dysfunction in patients with combat-related post-traumatic stress disorder: a double-blind, randomized and placebo-controlled studyBJU INTERNATIONAL, Issue 3 2009Mohammad Reza Safarinejad OBJECTIVE To evaluate the safety and efficacy of sildenafil citrate for treating erectile dysfunction (ED) in patients with combat-related post-traumatic stress disorder (PTSD). PATIENTS AND METHODS In all, 266 combat-exposed war veterans with ED (aged 37,59 years) were recruited. They met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for PTSD according to the Structured Clinical Interview for Patients, Investigator Version. The patients were also evaluated with the Clinician-Administered PTSD Scale, both to establish the diagnosis of PTSD and to measure symptom severity. Only patients with psychogenic ED were included in the study. Patients with comorbid conditions (diabetes mellitus, hypercholesterolaemia, hypertension, Peyronie's disease) and smokers of more than five cigarettes daily were excluded. The patients were randomly divided into a group of 133 who received 100 mg of on-demand sildenafil 0.75,2 h before sexual stimulation, and 133 who received placebo. Patients were asked to use ,16 doses or attempts at home. The efficacy of the treatments was assessed every four attempts during treatment, and at the end of the study, using responses to the 15-question International Index of Erectile Function (IIEF), Sexual Encounter Profile diary questions 2 and 3, Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire, patients' event logs of sexual activity, and a Global Assessment Question about erections. RESULTS Sildenafil did not produce significantly and substantially greater improvement than placebo in each of the primary and secondary outcome measures (P = 0.08). A normal EF domain score (,26) at endpoint was reported by 13 (9.8%), and 11 (8.3%) of patients on the sildenafil and placebo regimens, respectively (P = 0.09). Patients treated with sildenafil had no statistically significantly greater improvement in the five sexual function domains of the IIEF questionnaire than those treated with placebo (P = 0.08). The incidences of treatment-emergent adverse events were significantly greater in the sildenafil arm than in the placebo group (P = 0.01). CONCLUSIONS Sildenafil is no better than placebo in treating PTSD-emergent ED. Further randomized clinical trials are warranted in combat veterans and other populations with PTSD to better elucidate the role of phosphodiesterase type 5 inhibitors in treating PTSD-emergent ED. [source] Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionalityBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2002Donald J. Nichols Aims, To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods, Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results, The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36,47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19,38). Systemic exposure, as assessed by the mean area under the plasma concentration,time curve (AUC), was reduced by 11% (90% CI: 6,16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25,200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions, Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25,200 mg, systemic exposure increased in a slightly greater than dose-proportional manner. [source] Sildenafil reduces alcohol-induced gastric damage: just say ,NO'BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2008R Duffin Although sildenafil (Viagra) and other phosphodiesterase V (PDE V) inhibitors are increasingly recognized for their use in the treatment of male erectile dysfunction and perhaps more recently pulmonary artery hypertension, less is known of their potential beneficial effects in other situations. Medeiros et al., in the current issue of the British Journal of Pharmacology, report that sildenafil dramatically reduces alcohol-induced gastric damage in rats. The authors provide convincing evidence that such protection not only occurs via the nitric oxide (NO)/cGMP pathway, but also involves regulation of ATP-sensitive potassium channels. Therefore, in addition to exerting anti-impotence efficacy, PDE V inhibitors may provide significant beneficial effects from mucosal injury induced by alcohol. British Journal of Pharmacology (2008) 153, 623,624; doi:10.1038/sj.bjp.0707642; published online 17 December 2007 [source] Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2004Orsolya Nagy Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg,1) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140±52 vs 437±127% and episodes of ventricular tachycardia 4.0±3.2 vs 19.3±7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST-segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia-induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise. British Journal of Pharmacology (2004) 141, 549,551. doi:10.1038/sj.bjp.0705658 [source] Inhibition of neuroeffector transmission in human vas deferens by sildenafilBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2000Pascual Medina Sildenafil (0.1,30 ,M), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1,100 ,M), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1,100 ,M) had no effect on neurogenic contractions. The inhibition induced by sildenafil was not modified by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (1,30 ,M) but it was abolished by the K+ channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 ,M) and charybdotoxin (0.1 ,M). Sildenafil, zaprinast and SNP did not affect the contractions induced by noradrenaline. SNP (10 ,M) caused elevation of cyclic GMP levels that was potentiated by sildenafil (10 ,M) and zaprinast (100 ,M). ODQ (10 ,M) inhibited the increase in cyclic GMP. Sildenafil inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca2+ -activated K+ channels. British Journal of Pharmacology (2000) 131, 871,874; doi:10.1038/sj.bjp.0703657 [source] The Extracellular Signal-Regulated Kinase Is Involved in the Effects of Sildenafil on Pulmonary Vascular RemodelingCARDIOVASCULAR THERAPEUTICS, Issue 1 2010Zhen Zeng Pulmonary hypertension is a group of diseases comprising vascular constriction and obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, for example, sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats. We investigate the mechanisms of sildenafil on the pulmonary vascular remodeling of pulmonary hypertension induced by monocrotaline (MCT) in rats. Thirty Sprague-Dawley rats (weighing 200,220 g) were administered with MCT abdominal cavity injection or equivalent volume of normal saline (NS) (which were treated as C group n = 10) to induce pulmonary hypertension model. Fourteen days later, 20 MCT treated rats were randomly fed with sildenafil (25mg/kg/day) or placebo as S, P group (10 rats for each group), respectively. Another 6 weeks later, mean pulmonary artery pressure (mPAP), index of right ventricular hypertrophy (RV/LV+S) of all animals were measured under general anesthesia. Pulmonary tissue was collected to investigate pathological features of pulmonary arteries and to measure protein expression of ERK1/ERK2 and MKP1. After 6 weeks, there were significant elevated mPAP and RV/LV+S in both P and S groups. The ratio of wall thickness to vessel diameter in pulmonary arteries with diameters <200 ,m were increased in both P and S groups. But the ratio of wall thickness to vessel diameter was smaller in S group than that in P group. The phosphorylation level of ERK1/ERK2 were elevated in both P and S groups, but the level of phosphorlation ERK1/ERK2 were lower in S group than that in P group. Intriguingly, the expression level of MKP1 was significantly increased in both S and P groups, while it was higher in S group than that in P group. The Sildenafil can decrease mPAP and inhibit the progress of pulmonary vascular remodeling in pulmonary hypertension rats. The ERK-MAP kinase signaling pathway might play a role during this process. [source] Xanthine-analog, KMUP-2, enhances cyclic GMP and K+ channel activities in rabbit aorta and corpus cavernosum with associated penile erectionDRUG DEVELOPMENT RESEARCH, Issue 3 2002Rong-Jyh Lin Abstract The pharmacological properties of KMUP-2 were examined in isolated rabbit aorta and corpus cavernosum smooth muscle (CCSM). KMUP-2 caused relaxations that were attenuated by removed endothelium, high K+, and pretreatment with the soluble guanylate cyclase (sGC) inhibitors methylene blue (10 ,M) and ODQ (1 ,M), a NOS inhibitor, L-NAME (100 ,M), a K+ channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 ,M), a voltage-dependent K+ channel blocker 4-AP (100 ,M), and the Ca2+ -dependent K+ channel blockers apamin (1 ,M) and charybdotoxin (ChTX, 0.1 ,M). The relaxant responses of KMUP-2 (0.01, 0.05, 0.1 ,M) together with a PDE inhibitor, IBMX (0.5 ,M), had additive effects on rabbit aorta and CCSM. Additionally, KMUP-2 (100 ,M) also affected cGMP metabolism, due to its inhibiting activity on PDE in human platelets. KMUP-2 (0.1,100 ,M) further induced an increase of intracellular cGMP levels in the primary cultured rabbit aortic and CCSM cells. These increases in cGMP content were abolished in the presence of methylene blue (100 ,M) and ODQ (10 ,M). Obviously, the relaxant effects of KMUP-2 on rabbit isolated tissues are more sensitive in CCSM than in aorta. Moreover, KMUP-2 also stimulated NO/sGC/cGMP pathway and subsequent elevation of cGMP by blockade of PDE and enhanced opening of K+ channels in rabbit aorta and CCSM. KMUP-2 (0.2, 0.4, 0.6 mg/kg), similar to KMUP-1 and sildenafil, caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. It is concluded that both the increases of cGMP and the opening activity of K+ channels play prominent roles in KMUP-2-induced aortic smooth muscle and CCSM relaxation and increases of ICP in rabbits. Drug Dev. Res. 55:162,172, 2002. © 2002 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||