sildenafil-citrate and Diabetes-Mellitus--Type-2

Type 2 diabetes (T2D) is one of the major risk factors for developing cardiovascular disease and the resultant devastating morbidity and mortality. The key features of T2D are hyperglycemia, hyperlipidemia, insulin resistance, and impaired insulin secretion. Patients with diabetes and myocardial infarction have worse prognosis than those without T2D. Moreover, obesity and T2D are recognized risk factors in developing severe form of COVID-19 with higher mortality rate. The current lines of drug therapy are insufficient to control T2D and its serious cardiovascular complications. Phosphodiesterase 5 (PDE5) is a cGMP specific enzyme, which is the target of erectile dysfunction drugs including sildenafil, vardenafil, and tadalafil. Cardioprotective effects of PDE5 inhibitors against ischemia/reperfusion (I/R) injury were reported in normal and diabetic animals. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug and its hyperglycemia-controlling effect in diabetic patients is also under investigation. This review provides our perspective of a potential use of combination therapy of PDE5 inhibitor with HCQ to reduce cardiovascular risk factors and myocardial I/R injury in T2D. We previously observed that diabetic mice treated with tadalafil and HCQ had significantly reduced fasting blood glucose and lipid levels, increased plasma insulin and insulin-like growth factor-1 levels, and improved insulin sensitivity, along with smaller myocardial infarct size following I/R. The combination treatment activated Akt/mTOR cellular survival pathway, which was likely responsible for the salutary effects. Therefore, pretreatment with PDE5 inhibitor and HCQ may be a potentially useful therapy not only for controlling T2D but also reducing the rate and severity of COVID-19 infection in the vulnerable population of diabetics.

Topics: Animals; COVID-19; COVID-19 Drug Treatment; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hydroxychloroquine; Hyperglycemia; Insulin Resistance; Male; Mice; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride

Erectile dysfunction (ED) is a well-known entity with determined risk factors, which generally has a negative impact on quality of life. Obstructive sleep-disordered breathing (SDB), often referred to as obstructive sleep apnea, stands among the possible risk factors for ED.. Literature review suggests that SDB induces a spectrum of abnormalities in neural, hormonal, and vascular regulation that may contribute to the development of ED. While more studies are required to imply SDB as a risk factor for ED, several case series and expert opinion have contributed evidence for a causal relationship.. In clinical practice, men presenting with symptoms of sexual dysfunction often have concomitant sleep disorders requiring treatment. There is now evidence to suggest that treating SDB may be an effective treatment for ED. It is the authors' opinion that patients with erectile dysfunction would benefit from a sleep evaluation.

Topics: Aged; Cardiovascular Diseases; Continuous Positive Airway Pressure; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Obesity; Phosphodiesterase Inhibitors; Piperazines; Prevalence; Pulmonary Disease, Chronic Obstructive; Purines; Quality of Life; Risk Factors; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfones

Vascular dysfunction is a common feature in end-organ complications of type 2 diabetes mellitus (T2DM). The endothelium-specific receptor tyrosine kinase Tie2 and its ligand, angiopoietin-1 (Ang1), participate in the processes of vessel repair, renewal, and maturation. However, their dysregulation in T2DM has seldom been investigated.. To examine the relationship between angiogenic Tie2-expressing monocytes (TEMs) and Ang1, and their pharmacological modulation by the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, in T2DM and in db/db mouse model.. Randomized, double-blind, placebo-controlled study.. db/db male mice were randomly assigned to receive 8 weeks of sildenafil or vehicle. Diabetic men were randomly assigned to receive 4 weeks of sildenafil or placebo.. Peripheral blood cells were investigated by flow cytometry to quantify inflammatory myeloid CD11b+ Gr1+ cells and proangiogenic TEMs in mice and classical CD14++CD16neg monocytes and proangiogenic TEMs in humans at baseline and after treatment. In vitro human tube formation assay was used to test serum angiogenic potential.. We show that TEMs and Ang1 are defective in mouse and human models of diabetes and are normalized by PDE5i treatment. Serum angiogenic properties are impaired in diabetes because they do not support the in vitro formation of capillary-like structures, but they are reestablished by in vivo PDE5i treatment.. Restoring a more physiological Tie2-Ang1 axis with sildenafil reestablishes serum angiogenic properties in diabetes, promoting angiogenic homeostasis.

Topics: Aged; Angiopoietin-1; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Double-Blind Method; Humans; Male; Mice; Middle Aged; Monocytes; Neovascularization, Physiologic; Phosphodiesterase 5 Inhibitors; Placebos; Receptor, TIE-2; Sildenafil Citrate; Treatment Outcome

To investigate the safety and efficacy of pancreatic kininogenase combined with sildenafil in the treatment of erectile dysfunction(ED) in type 2 diabetes mellitus (DM) patients in the high-altitude area.. This study included 93 ED patients with type 2 DM, all residents of the Xining area 1500 meters above sea level. We randomly divided them into an experimental group (n = 48) and a control group (n = 45), the former treated with pancreatic kininogenase(120 u, tid) and sildenafil (25 mg, qd at bedtime), while the latter with sildenafil only (25 mg, qd at bedtime).After 4 and 8 weeks of medication, we obtained the penile hemodynamic parameters,IIEF-5 scores, and sexual intercourse satisfaction(SIS) scores and compared them between the two groups of patients.. There were no statistically significant differences in age or DM course between the two groups of patients (P >0.05).Compared with the baseline, both the experimental and control groups showed remarkably improvement inthe IIEF-5 score (8.81 ± 2.06 vs 11.54 ± 7.72 and 8.29 ± 1.91 vs 9.37± 1.65, P <0.05), SIS score (3.35 ± 2.43vs6.83± 2.61and 3.41 ± 2.38 vs 4.92± 2.49, P <0.05), and penile hemodynamic parameters obtained by color duplex Doppler ultrasonography(P <0.05), with significant differences between the two groups in the IIEF-5 score (11.54 ± 7.72 vs 9.37± 1.65, P <0.05) and SIS score (6.83± 2.61 vs 4.92± 2.49, P <0.05) but not in the penile hemodynamic parameters (P >0.05). Even more remarkable improvement was observed at 8 weeks in the experimental and control groups in the IIEF-5 score (19.29± 1.85 and 15.43± 1.74)(P <0.05), SIS score (11.73 ± 2.57 and 6.55± 2.71) (P <0.05), and penile hemodynamic parameters(P <0.05), all with significant differences between the two groups (P <0.05).. Pancreatic kininogenase combined with sildenafil has a better clinical effect than sildenafil alone on ED in type 2 DM patientsin the high-altitude area.. 目的： 探讨胰激肽原酶肠溶片联合西地那非治疗高海拔地区2型糖尿病合并勃起功能障碍(ED)患者的安全性及疗效。方法： 选择青海西宁地区糖尿病合并ED患者93例，随机分成两组，试验组(48例)服用胰激肽原酶肠溶片（120 u，3次/d）联合小剂量西地那非规律服用（25 mg，每晚1次），对照组(45例) 小剂量西地那非规律服用（25 mg，每晚1次），两组治疗4、8周后评价两组阴茎彩色多普勒超声（CDDU）检查、国际勃起功能指数(IIEF-5)、性交满意度。结果： 患者年龄及糖尿病病程两组间均无显著差异(P>0.05)。治疗4周：试验组和对照组治疗前后IIEF-5评分［(8.81±2.06)分 vs (11.54±7.72)分和(8.29±1.91)分 vs (9.37±1.65)分］、SIS［(3.35±2.43)分 vs (6.83±2.61)分和(3.41±2.38)分 vs (4.92±2.49)分］、CDDU均有显著差异(P<0.05)，两组间IIEF-5评分［(11.54±7.72)分 vs (9.37±1.65)分］和SIS［(6.83±2.61)分 vs (4.92±2.49)分］有显著差异(P<0.05)，而CDDU参数无差异(P>0.05)。治疗8周：试验组和对照组治疗前后IIEF-5评分［(8.81±2.06)分 vs (19.29±1.85)分和(8.29±1.91)分 vs (15.43±1.74)分］均有显著差异 (P<0.05)，两组间IIEF-5评分［(19.29±1.85)分 vs (15.43±1.74)分］、SIS［(11.73±2.57)分 vs (6.55±2.71)分］、CDDU参数均有显著差异(P<0.05)。结论： 胰激肽原酶肠溶片联合西地那非治疗高海拔地区2型糖尿病合并ED患者具有一定临床疗效，且较单一西地那非治疗更为有效。.

Topics: Aged; Altitude; Coitus; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Erectile Dysfunction; Humans; Kallikreins; Male; Pancreas; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Treatment Outcome

Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients.. To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs).. Randomized, double-blind, placebo-controlled study in type 2 diabetes.. A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected.. Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT.. Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile.. Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.

Topics: Adiposity; Adult; Aged; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Type 2; Double-Blind Method; Flow Cytometry; Humans; Male; Mice; Mice, Obese; MicroRNAs; Middle Aged; Obesity, Abdominal; Phosphodiesterase 5 Inhibitors; Real-Time Polymerase Chain Reaction; Sildenafil Citrate; Sirtuin 1

Endothelial dysfunction (ED) plays a role in diabetic cardiovascular complications. Hyperglycemia increases cytockines involved in vascular inflammation. Inhibition of phosphodiesterase type 5 (PDE5) exerts a relaxation on corpora cavernosa and has cardioprotective properties. The effect of chronic sildenafil treatment, on ED markers and metabolic parameters in a non-randomized study on men with type 2 diabetes (T2DM), was investigated.. Twenty-eight T2DM patients (61.2 ± 7.8 years, hemoglobin A1c (HbA1c) 7.9 ± 1.3%, duration of diabetes 11.5 ± 7.8 years) were treated with sildenafil 100 mg/d for 3 months. Baseline and postprandial glycemia, insulin, HbA1c, HOMA index, lipids, glomerular filtration rate, homocysteine were assessed at each visit. P-selectin (CD62P), CD14/42b, CD14/41, ICAM (CD54), PECAM (CD31) and CD11b/CD18, were evaluated, after monocyte isolation with flow-cytometry, before and after treatment.. After 3 months, sildenafil decreased P-selectin (p < 0.05), post-prandial glycemia (p < 0.01), HbA1c (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and increased high-density lipoprotein (p < 0.05).. PDE5 inhibition, in T2DM patients, reduces the endothelial function marker P-selectin and exerts a beneficial effect on glycometabolic control.

Topics: Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Endothelium, Vascular; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Lipids; Male; Middle Aged; P-Selectin; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Vasodilator Agents

We evaluated the effect of lifestyle modifications and glycemic control on the efficiency of sildenafil citrate in patients with type-2 diabetes (T2DM) and erectile dysfunction (ED).. Eighty-three men with ED due to T2DM were included in the study. The Group 1 (n = 41) patients received lifestyle modifications (diet and exercise), and medical treatment for intensive glycemic control. In Group 2 (n = 42), in addition to the intensive glycemic control, the patients were given sildenafil citrate® 100 mg for 2-3 per weeks. The changes in ED were compared between the two groups after three months of treatment.. The mean age was 54.9 ± 9.1 (26-75) years. An increase in the IIEF-5 scores was observed in 23 of 41 patients in Group 1 (44.2%) and 29 of 42 in Group 2 (55.8%). When the changes of the IIEF-5 scores were evaluated, the mean increase was 2.5 in Group 1, and 5.0 in Group 2 (p = 0.012). The mean IIEF changes according to the duration of diabetes were 4.8 in <5 years, 3.6 in 5-10 years and 1.6 in >10 years (p = 0.021).. Glycemic control and lifestyle changes are not solely adequate for a better sexual function in ED due to diabetes, and sildenafil citrate should be used additionally.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Erectile Dysfunction; Glycemic Index; Humans; Male; Middle Aged; Risk Reduction Behavior; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

To evaluate the efficacy and safety of combination therapy of sildenafil plus vacuum erection devices in men with type 2 diabetes mellitus with moderate to severe erectile dysfunction who are dissatisfied with the results of using sildenafil alone.. The study included 66 diabetes mellitus patients presenting erectile dysfunction for at least 6 months and dissatisfied with the use of 100 mg sildenafil monotherapy. The patients were randomized in two groups. Those in group A (n = 33) were instructed to use a vacuum erection device only, whereas those in group B (n = 33) were treated with combination therapy, including sildenafil 100 mg and a vacuum erection device. Erectile function was evaluated subjectively using the International Index of Erectile Function, Sexual Encounter Profile questionnaire questions 2 and 3 at visit 1 (baseline; study entry), visit 2 (4 weeks after baseline), and visit 3 (12 weeks after baseline; study end).. There were no significant differences in average patient age, duration of diabetes, duration of erectile dysfunction, baseline International Index of Erectile Function scores, hypertension, blood testosterone, smoking and alcohol consumption between two groups. Mean International Index of Erectile Function scores were significantly higher for group B at the 1-month (14.86 ± 2.17 vs 12.41 ± 2.63; P < 0.0001) and 3-months (17.53 ± 2.95 vs 14.29 ± 2.81; P < 0.0001) visits. Men in group B had better successful penetration (73.3% vs 46.6%) and successful intercourse (70% vs 46.6%) at 3 months compared with group A.. Combined use of sildenafil and vacuum erection device therapy significantly enhances erectile function, and it is well tolerated by diabetes mellitus patients not responding to first-line sildenafil alone.

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Erectile Dysfunction; Follow-Up Studies; Humans; Male; Middle Aged; Penile Erection; Piperazines; Purines; Retrospective Studies; Sexual Behavior; Sildenafil Citrate; Sulfonamides; Surveys and Questionnaires; Treatment Failure; Vacuum; Vasodilator Agents

Erectile dysfunction (ED) is a multifactorial disease associated with vascular dysfunction, low nitric oxide (NO) bioavailability, and oxidative stress. However, it is not known whether low NO bioavailability and oxidative stress affect the responsiveness of ED patients to sildenafil. We tested this hypothesis by studying 28 healthy subjects (control group), 26 patients with ED without comorbidities (ED group), and 18 patients with ED and diabetes mellitus (ED/DM group). The International Index for Erectile Function (IIEF) questionnaire was used to assess the erectile function of all participants, and their responsiveness to sildenafil was assessed as the percentage of change in the five-item version of IIEF score before and after sildenafil treatment. Levels of whole blood nitrite, antioxidants markers (ferric reducing ability of plasma (FRAP) and reduced glutathione), and oxidative stress markers (thiobarbituric acid reactive substance and protein carbonyl) were determined. We found a negative correlation between whole blood nitrite levels and the responses to sildenafil in both ED groups (P<0.05). FRAP correlated negatively with the responses to sildenafil in the ED/DM group (P<0.05). No other significant associations were found. Our findings show evidence that low NO bioavailability is associated with better responses to sildenafil in patients with ED (with or without DM).

Topics: Adult; Aged; Biological Availability; Diabetes Mellitus, Type 2; Erectile Dysfunction; Glutathione; Humans; Male; Middle Aged; Nitric Oxide; Nitrites; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Carbonylation; Purines; Sildenafil Citrate; Sulfones; Thiobarbituric Acid Reactive Substances; Treatment Outcome

cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy.. Fifty-nine diabetic men (60.3 ± 7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [σ], -12.6 ± 3.1; increased left ventricular [LV] torsion [θ], 18.4 ± 4.6°; and increased ratio of LV mass to volume, 2.1 ± 0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro-B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion (Δθ: sildenafil, -3.89 ± 3.11° versus placebo, 2.13 ± 2.35°; P<0.001) and strain (Δσ: sildenafil, -3.30 ± 1.86 versus placebo, 1.22 ± 1.84; P<0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5 ± 11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-β were the only markers affected by active treatment (Δmonocyte chemotactic protein-1: -75.30 ± 159.28 pg/mL, P=0.032; Δtransforming growth factor-β: 5.26 ± 9.67 ng/mL, P=0.009). No changes were found in endothelial function, afterload, or metabolism.. The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action.

Topics: Aged; Cardiac Imaging Techniques; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Follow-Up Studies; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Torsion, Mechanical; Treatment Outcome; Ventricular Remodeling

We investigated changes in serum biomarkers of vascular function after short-term, continuous sildenafil dosing in men with type 2 diabetes with erectile dysfunction.. Men with erectile dysfunction associated with type 2 diabetes mellitus were randomized to receive continuous, daily sildenafil (50 mg for 1 week run-in and 100 mg for 3 weeks) (148), or placebo (144) for 4 weeks (phase I) and then sildenafil (25, 50 or 100 mg) on demand for 12 weeks (phase II). Blood draws at baseline and after phases I and II were analyzed for cyclic guanosine monophosphate (endothelial function marker), 8-isoprostane (oxidative stress marker), and interleukin-6 and interleukin-8 (inflammatory cytokines). Primary and secondary erectile function outcome variables were affirmative responses on Sexual Encounter Profile question 3 (ability to maintain erection sufficient for sexual intercourse) and Erection Hardness Score, respectively.. Serum cyclic guanosine monophosphate levels were increased in the sildenafil group relative to the placebo group at 4 (p <0.01) and 16 (p <0.05) weeks, correlating with affirmative responses to Sexual Encounter Profile question 3 at the 4-week interval only (p <0.05). Serum 8-isoprostane levels were decreased to a nonsignificant degree in the sildenafil group at 4 weeks with no further change at 16 weeks, whereas interleukin-6 and interleukin-8 levels were unchanged at either interval, and these levels were unassociated with erectile function outcomes.. These data suggest that short-term, continuous sildenafil treatment causes systemic endothelial function to be enhanced and remain so for a duration after its discontinuation. However, they do not indicate any influence of this treatment on systemic oxidative stress or inflammation, or an effect on long-term erectile function improvement.

Topics: Adult; Aged; Biomarkers; Cyclic GMP; Diabetes Complications; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; Erectile Dysfunction; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study.. A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured.. Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo.. Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS.

Topics: Autonomic Nervous System; Baroreflex; Blood Pressure; Brachial Artery; Cardiovascular System; Cross-Over Studies; Diabetes Mellitus, Type 2; Erectile Dysfunction; Heart Rate; Humans; Male; Patient Selection; Phosphodiesterase Inhibitors; Piperazines; Placebos; Posture; Pulse; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Diabetic patients have a reduced endothelial response to phosphodiesterase-5 inhibitors. The aim of this study was to determine the effects of chronic therapy with sildenafil on endothelial function in patients with Type 2 diabetes mellitus (DM2).. In a double-blind, placebo-controlled parallel design, 20 patients without erectile dysfunction randomly received a loading dose of sildenafil (100 mg) for 3 days, followed by either sildenafil 25 mg three times a day (t.d.s.) for 4 weeks or sildenafil 25 mg t.d.s. for 4 days followed by placebo t.d.s. for 3 weeks.. After 1 week, flow-mediated dilatation (FMD) improved significantly (> 50% compared with baseline) in patients allocated to both sildenafil arms (62 and 64%, respectively). In patients allocated to chronic sildenafil, a progressive increase in percentage of patients with FMD improvement was noted (78, 86 and 94% at 2, 3 and 4 weeks, respectively) while a progressive decrease in the placebo group occurred (45, 18 and 6% at 2, 3 and 4 weeks, respectively). At the end of the study, a significant improvement in FMD compared with baseline was noted after chronic sildenafil (FMD from 6.8 +/- 0.5 to 12.5 +/- 0.7%, P = 0.01 vs. baseline). A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found after chronic sildenafil; significant changes from baseline in C-reactive protein, interleukin 6, intercellular adhesion molecule and vascular adhesion molecule levels were also found.. In DM2 patients, daily sildenafil administration improves endothelial function and reduces markers of vascular inflammation, suggesting that the diabetes-induced impairment of endothelial function may be improved by prolonged phosphodiesterase-5 inhibition.

Topics: Adult; Aged; Biomarkers; Brachial Artery; C-Reactive Protein; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Humans; Interleukin-6; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation; Vasodilator Agents

Sildenafil citrate is a specific inhibitor of phosphodiesterase (PDE) type-5 and represents a powerful therapy for male erectile and fertility dysfunctions of different etiologies. Present study demonstrates whether sildenafil administration modifies seminal parameters in diabetic neuropathic patients. In this investigation 50 insulin dependent (IDDM) and 50 non insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and 50 age matched non diabetic male controls were selected. Every male had age between 20 to 65 years with duration of diabetes distributed over 1 to 20 years. Treatment with 100 mg of oral sildenafil citrate on seminal parameters was evaluated by semen analysis in these patients. In both IDDM and NIDDM diabetic neuropathic patients, chronic sildenafil treatment exhibited a significant decrease in total sperm output and sperm concentration (p<0.001). On the other hand, sperm motility and semen volume were found to be increased by about 40% and 48% respectively in these patients, where as sperm morphology and quality of sperm motility remained unaffected. However both types of non neuropathic diabetics showed a non significant difference in all the above mentioned parameters when compared with the untreated groups and their respective control subjects. A comparison between IDDM and NIDDM neuropathic and non neuropathic diabetic groups further indicated a non significant difference in all the parameters of semen analysis. These findings suggest a chronic neuro physiological effect of sildenafil treatment on male fertility profile exclusively in diabetic neuropathic condition with an improvement in testicular function which was probably arrested due to some kind of testicular hyperplasia resulted by testicular necrosis and promoted spermatogenesis. Sildenafil seems to be associated with an improvement in the entire smooth musculature of reproductive tract and testicular morphology which was altered due to neuropathy like a reduction in excess accumulation of interstitial collagen and calcification in the smooth muscles of seminiferous tubules which made them rigid leading to atonia of bladder and urethra which resulted in partial or retrograde ejaculation associated with a decreased sperm motility. Sildenafil treatment returned back the spermatogenesis to normal with a positive influence on sperm motility and ejaculate volume in these neuropathic patients irrespective of the type of diabetes.

Topics: Administration, Oral; Adult; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Erectile Dysfunction; Fertility; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sperm Count; Sperm Motility; Spermatogenesis; Spermatozoa; Sulfones; Treatment Outcome

Sildenafil citrate has shown to display beneficial cardiovascular effects, suggesting that it may have other systemic benefits involving the endothelium. There is little data regarding the long-term use of this drug and the effects of this on different organs.. The primary aim of this study was to determine whether sildenafil citrate diminishes concentrations of microalbuminuria and percentage of A1c in patients with type 2 diabetes.. A double-blind, randomized, controlled trial in 40 male patients, age 35-50, with type 2 diabetes. Subjects received sildenafil citrate 50 mg daily (n=20) or placebo (n=20) for 30 days. Levels of hs-CRP, microalbuminuria, homocysteine, A1c and erectile function were measured at baseline and to the end of the study.. Men that received sildenafil citrate displayed a significant decrease in the microalbuminuria concentrations (p<0.01) versus baseline, (p=0.02) versus placebo and A1c (p<0.01) versus baseline, (p=0.01) versus placebo. In addition, we observed a significant increase in the total IIEF score after 30 days of treatment (p<0.01) versus baseline, (p<0.01) versus placebo.. The administration of 50mg of sildenafil citrate for 30 consecutive days diminishes microalbuminuria and the percentage of A1c in patients with type 2 diabetes.

Topics: Adult; Albuminuria; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Homocysteine; Humans; Male; Middle Aged; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To investigate the synergic effect of propionyl L-carnitine (PLC) plus sildenafil in reducing monocyte oxidative activity and endothelial dysfunction markers in diabetic patients with erectile dysfunction (ED).. Thirty-two type 2 diabetic patients with ED (according to the International Index of Erectile Function-5 [IIEF-5]) were randomized to receive PLC (2 g/d) alone (n=8) or combined with sildenafil (50 mg/d twice weekly) (n=8), sildenafil alone (50 mg/d twice weekly) (n=8), or placebo (n=8) in a double-blind, fixed-dose study. Monocyte oxidative activity (stimulation index [SI]), intercellular adhesion molecule-1 [ICAM-1], P-selectin, advanced glycation end product (AGE) levels, Doppler sonography (recording peak systolic velocity [PSV]; end diastolic velocity [EDV]; systolic wave time [SWT]; resistive index [RI]), and IIEF score were evaluated before and after 12 wk of treatment; IIEF-5 was evaluated again 4 wk posttreatment.. SI was reduced by treatment with PLC alone or combined with sildenafil (p<0.05). In patients treated with PLC plus sildenafil, a decrease in ICAM-1, P-selectin, and EDV values was observed compared with patients treated with sildenafil alone (p<0.05, p<0.01, p<0.001, respectively). IIEF-5 improved in all patients treated with PLC plus sildenafil or sildenafil alone (p<0.03, p<0.05, respectively). Four weeks posttreatment, patients treated with PLC plus sildenafil maintained the improvement of the IIEF-5 compared with patients on sildenafil alone (p=0.05). In patients on PLC treatment (with or without sildenafil), SI was correlated with IIEF-5 (p<0.001), glycemia with STW (p<0.03), and AGEs with IIEF-5 (p<0.01).. PLC plus sildenafil was more effective in reducing SI and endothelial dysfunction markers in patients with type 2 diabetes and ED.

Topics: Aged; Antioxidants; Biomarkers; Carnitine; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Erectile Dysfunction; Glycated Hemoglobin; Humans; Male; Middle Aged; Monocytes; Phosphodiesterase Inhibitors; Piperazines; Purines; Reactive Oxygen Species; Sildenafil Citrate; Sulfones

Assess the effectiveness of sildenafil in Asian males with erectile dysfunction (ED) and one or more of the co-morbidities, mild-to-moderate hypertension, dyslipidemia, and diabetes.. A six-week, double-blind, randomized, placebo-controlled, multicenter study was carried out in Thailand, Malaysia and Singapore. One hundred and fifty five male subjects were randomized (2:1) to sildenafil (n = 104) or placebo (n = 51). Sildenafil was started at 50 mg and increased (100 mg) or decreased (25 mg) at week 2 if necessary.. On the primary efficacy endpoint, sildenafil-treated subjects had significantly better scores on the International Index of Erectile Function (IIEF) questions 3 and 4 than placebo (p < 0.001, both questions). When accumulated into IIEF domains, all five domains were significant in favor of sildenafil. In addition, sildenafil-treated subjects were more satisfied with treatment and had a higher intercourse success rate. The majority of adverse events were mild in severity; the most commonly reported treatment-related events were dizziness (7.7%) and tinnitus (2.9%).. Sildenafil (25, 50, and 100 mg) was found to be an effective, safe, and well-tolerated treatment for ED in the present study population of Thai, Malaysian, and Singaporean males who also had increased cardiovascular risk

Topics: Asian People; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Erectile Dysfunction; Humans; Hypertension; Malaysia; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Assessment; Risk Factors; Sildenafil Citrate; Singapore; Sulfones; Thailand; Treatment Outcome

To assess efficacy of sildenafil citrate in treatment of erectile dysfunction: effect of type 2 diabetes.. A total of 466 male patients with erectile dysfunction (ED) were enrolled in this study. Of them 382 were diabetic and 84 were non-diabetic. Patients were screened for ED using the erectile function domain of the International Index for Erectile Function (IIEF). Patients underwent routine laboratory investigations, in addition to total testosterone and prolactin assessment. To assess the effect of diabetes on efficacy of sildenafil, we compared the pre and post sildenafil responses to erectile function domain, Q3, Q4. Overall satisfaction and global efficacy question (GEQ) were also assessed.. Mean age +/- S.D. was 53 +/- 8.4 and 49.7 +/- 10.6 years for patients with and without diabetes respectively. There were significant associations between increased severity of ED and longer duration, poor metabolic control and presence of more than one diabetes-related complication (p < 0.05 for each). Differences were significant between pre and post sildenafil administration regarding erectile function domain, Q3, Q4 (p < 0.05 for each). In the non-diabetic patients the GEQ and the overall satisfaction were significantly higher than in diabetics (p < 0.05 for each). Global efficacy question was significantly low in patients with fair and poor metabolic control, longer duration of diabetes, and patients with diabetic complications (p < 0.05 for each).. Sildenafil is an effective treatment for diabetic patients with ED. Although the efficacy of sildenafil was negatively affected by factors as poor control and longer duration of diabetes and presence of more than one diabetes-related complication, however, the global efficacy and the overall patients' satisfaction were high.

Topics: Analysis of Variance; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Flow-mediated dilatation (FMD), induced by occlusion of the brachial artery, is an index of nitric oxide-dependent endothelial function that is impaired in patients with type 2 diabetes. Sildenafil (Viagra) is an inhibitor of phosphodiesterase 5 (PDE-5), which is used for management of erectile dysfunction in a broad range of patients, including those with type 2 diabetes. Its effects on endothelial function in these patients have not been previously assessed.. We assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on FMD in patients with type 2 diabetes. We performed a double-blind, placebo-controlled cross-over trial in 16 patients (14 of whom completed the study) with type 2 diabetes who had erectile dysfunction without overt clinical heart disease.. In these patients, the mean +/- SD brachial artery diameter (BAD) measured by ultrasound was 4.33 +/- 0.6 mm. After inducing FMD, the BAD increased 8% to 4.66 +/- 0.6 mm (P = 0.2). One hour after oral administration of sildenafil 25 mg, FMD increased the BAD significantly by 15% to 4.99 +/- 0.5 mm (P < or = 0.01), whereas it did not change with placebo (4.6 +/- 0.6 mm, P = 0.1). After treatment with sildenafil 25 mg daily for 2 weeks and testing 24 h after the last dose, the mean FMD was 14% (P = 0.01). In contrast, the mean FMD with placebo was 9% (P = 0.45).. We conclude that acute and prolonged sildenafil treatment has a favorable effect on brachial artery flow-mediated dilatation that persists for at least 24 h after the last dose. Further investigation is needed to determine whether this prolonged effect has clinical implications in patients with type 2 diabetes.

Topics: Adult; Brachial Artery; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Erectile dysfunction is a common complication in patients with diabetes mellitus, which impairs quality of life, decreases self-esteem and can affect partners relationships. Sildenafil improves nitric oxide-dependent relaxation of smooth muscle in corpora cavernosa--induced by an increase in cGMP via inhibition of phosphodiesterase 5.. Multicenter, randomized, double-blind, placebo-controlled study with flexible doses of sildenafil. The study was performed in 16 centers and recruited a total of 112 subjects with diabetes mellitus who had erectile dysfunction. At the start and end of the study, the following questionnaires were administered: International Index of Erectile Function (IIEF), Global Efficacy Assessment Question and Quality of Life Questionnaire (Fugl-Meyer). Of the 112 initially recruited patients, 92 received treatment, sildenafil in 44 and placebo in 48.. A clear improvement was observed in the capacity to achieve and maintain an erection; 55.3% diabetic patients receiving sildenafil had at least one successful sexual intercourse (15.6% in the placebo group). In addition, significant improvements were seen in other aspects of the sexual activity of treated subjects. Among those treated with sildenafil, 46.3% reported a clear improvement of erections as compared to their baseline conditions (i.e, prior to treatment) vs only 14.9% in the placebo group. The percentage of a successful intercourse clearly increased, from 6 to 49%. Sildenafil was well-tolerated. Side effects were mild and transient.. Sildenafil is an effective, safe treatment for erectile dysfunction in diabetic patients.

Topics: Adult; Aged; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Double-Blind Method; Erectile Dysfunction; Humans; Logistic Models; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Placebos; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Surveys and Questionnaires; Vasodilator Agents

Ninety percent of all men with diabetes have Type II (non-insulin-dependent) diabetes mellitus, and erectile dysfunction (ED) is common in this patient group. This study evaluated the effects of sildenafil on men with erectile dysfunction and Type II diabetes and compared the results with glycated haemoglobin concentrations and chronic diabetic complications.. Patients (mean age, 59 years) in this double-blind, placebo-controlled trial were randomised to sildenafil (25-100 mg; n = 110) or matching placebo (n = 109) for 12 weeks. Primary criteria for efficacy included questions 3 (achieving an erection) and 4 (maintaining an erection) from the International Index of Erectile Function (IIEF, score range, 0-5). Secondary outcome measures included a global efficacy question (GEQ), patient event logs, a life satisfaction checklist, and the remaining IIEF questions.. After 12 weeks, the mean scores for questions 3 and 4 had improved significantly in patients receiving sildenafil (3.42 +/- 0.23 and 3.35 +/- 0.24) compared with placebo (1.86 +/- 0.22 and 1.84 +/- 0.23; p < 0.0001). Similarly, the GEQ score was higher in the sildenafil (64.6 %) than the placebo group (10.5 %). Even when correlating efficacy with glycated haemoglobin concentrations ( < or = 8.3 % or > 8.3 %, the median concentration found in this study) or the number of diabetic complications (0 or > or = 1), the mean scores for the GEQ and questions 3 and 4 from the IIEF remained higher for all the sildenafil groups compared with the placebo groups (p < 0.0001).. Sildenafil was well-tolerated and effective in improving erectile dysfunction in men with Type II diabetes, even in patients with poor glycaemic control and chronic complications.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Double-Blind Method; Erectile Dysfunction; Glycated Hemoglobin; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

To evaluate the results of using Sildenafil in the form of an oral spray (Gent) for the treatment of erectile dysfunction (ED) in men with type 2 diabetes mellitus (DM) and prediabetes.. A total of 60 patients were divided into two groups of 30 people. The group 1 included patients with prediabetes, while group 2 consisted of patients with type 2 DM. All men had proven ED. The severity of ED was assessed using the International Index of Erectile Function (IIEF-5). To assess the state of penile blood flow, all patients underwent Doppler ultrasound before and after treatment. Patients with prediabetes used Sildenafil in the form of oral spray (Gent) 25 mg (2 doses) 1 time per day for 1 month, patients with type 2 diabetes received 50 mg (4 injections) every other day for 1 month. In addition, most of the subjects took metformin and followed diet therapy.. In patients of both groups, the administration of Sildenafil oral spray led to a decrease in body weight, waist circumference, a decrease in insulin and Hemoglobin A1C level without changing of hypoglycemic therapy in those with type 2 DM. In men with prediabetes, a decrease in fasting insulin levels was found. During treatment, half of the persons with impaired glucose metabolism had an increase in the testosterone level. According to IIEF-5, a decrease in the severity of ED in both groups of patients was seen. In men with prediabetes, the average IIEF-5 score increased from 15.98 to 21.57 points (p<0.05), while in patients with type 2 DM it improved from 12.18 to 18.44 points (p<0.05). Doppler ultrasound indicated a significant increase in the maximum systolic blood flow velocity and arterial resistivity index after treatment with Sildenafil oral spray in patients with both prediabetes and type 2 diabetes.. Sildenafil oral spray can be effectively used for the treatment of ED in men with type 2 DM and prediabetes.

Topics: Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Insulins; Male; Oral Sprays; Piperazines; Prediabetic State; Purines; Sildenafil Citrate; Treatment Outcome

Background In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphodiesterase 5 Inhibitors; Receptors, Adrenergic, beta-2; Sildenafil Citrate

Different adipose tissue (AT) depots are associated with multiple metabolic risks. Phosphodiesterase type 5 (PDE5) is involved in adipocyte physiology and PDE5 inhibition may affect adipogenesis and ameliorate white AT quality. The aim of this study is to investigate the distribution of AT and the composition of the stroma-vascular fraction (SVF) of subcutaneous AT (SAT) in type 2 diabetic mice after prolonged treatment with a PDE5 inhibitor, Sildenafil. 18 db/db mice were treated with Sildenafil or vehicle for 12 weeks. AT distribution was monitored and SAT was processed for isolation of SVF by flow cytometry. Sildenafil induced an overall reduction in AT, mainly in visceral AT (VAT), compared with SAT. In Sildenafil-treated mice, the mean change in body weight from baseline positively correlated with VAT, but not with SAT. Characterization of SVF of SAT showed an increase in the frequency of M2 macrophages and endothelial cells in treated mice. Sildenafil improved the maintenance of SAT homeostasis and distribution.

Topics: Adipocytes; Adipogenesis; Animals; Cell Plasticity; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Intra-Abdominal Fat; Mice; Obesity; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Stromal Cells; Subcutaneous Fat

To evaluate treatment response in men with erectile dysfunction (ED) and concomitant comorbidities.. Data were pooled from 42 placebo-controlled, flexible-dose sildenafil trials. In most trials, the sildenafil dose was 50 mg, taken ~1 hour before sexual activity but not more than once daily, with adjustment to 100 or 25 mg as needed. The overall population (N=9413) was stratified by age (<45, 46-64, ≥65 years). Treatment response was defined as a minimal clinically important difference (MCID) from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score of >2, >5 and >7 for men with mild, moderate and severe ED at baseline, respectively, or an IIEF-EF domain score ≥26 (no ED) at end-point.. In the overall population, treatment response using the IIEF-EF MCID definition was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (77% vs 33%), cardiovascular disease/hypertension only (71% vs 27%), diabetes only (63% vs 24%) or depression only (78% vs 29%). Using an IIEF-EF score ≥26, treatment response was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (49% vs 17%), cardiovascular disease/hypertension only (48% vs 12%), diabetes only (40% vs 12%) or depression only (60% vs 17%). With each definition, the treatment response for each age and comorbidity was significantly greater (P≤.0065) with sildenafil vs placebo.. The treatment response was significantly greater with sildenafil vs placebo in men with ED and each comorbidity regardless of age.

Topics: Aged; Cardiovascular Diseases; Depression; Diabetes Mellitus, Type 2; Erectile Dysfunction; Health Status; Humans; Hypertension; Male; Middle Aged; Remission Induction; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Vasodilator Agents

Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE) cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1) expression and reduction of capillary-like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG) neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these restorative processes.

Topics: Angiopoietin-1; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Male; Mice; Peripheral Nervous System Diseases; Receptor, TIE-2; Recovery of Function; Signal Transduction; Sildenafil Citrate; Treatment Outcome

Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P < 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41-2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93 ± 0.06, P < 0.05) and BAY 58-2667 (heme-independent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.

Topics: Animals; Arterial Pressure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Female; Guanylate Cyclase; Mesenteric Arteries; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfonamides; Vasodilation; Vasodilator Agents

Despite the fact that urogenito-sexual complications significantly impact the quality of life of diabetic patients, a robust in vivo experimental model is lacking. Bladder and erectile function in the Type 2 diabetic Goto-Kakizaki (GK) rat and responses to standard-of-care treatments for each disorder have been assessed. GK rats (n = 25, 18-wk-old, GK/Par colony) and age-matched Wistar rats (n = 23), characterized for their metabolic parameters, were used. Bladder function was assessed by cystometry in conscious rats treated by intravenous solifenacin (1 mg/kg). Subsequently, erectile function was assessed under anesthesia following electrical stimulation of the cavernous nerve in presence of intravenous sildenafil (0.3 mg/kg). GK rats displayed detrusor overactivity with a significant increase in frequency/amplitude of nonvoiding contractions during the filling phase, together with an increase in bladder capacity, intercontraction interval, voided volume, and maximal pressure of voiding contraction. Solifenacin significantly decreased parameters characterizing voiding contractions without modifying voiding efficiency. Erectile function in GK rats was markedly impaired and remained so after sildenafil treatment despite a significant improvement. GK rats display both bladder and erectile dysfunctions and respond at least partially to standard-of-care treatments for each disorder, thus representing a suitable model to investigate the pathophysiology and assess the efficacy of new therapeutic agents for Type 2 diabetes-associated bladder and erectile complications.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Erectile Dysfunction; Male; Penile Erection; Piperazines; Purines; Quinuclidines; Rats; Rats, Wistar; Sildenafil Citrate; Solifenacin Succinate; Sulfones; Tetrahydroisoquinolines; Urinary Bladder; Urinary Bladder Diseases; Urination; Urological Agents; Vasodilator Agents

The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase[PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treatinghy pertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats.. To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated.. HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil,tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA.. Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation ofHPRA and cGMP accumulation in HCC.. Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levelsin HCC from DMED.. Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with diabetes.

Topics: Arteries; Benzopyrans; Carbolines; Cyclic GMP; Diabetes Mellitus, Type 2; Drug Synergism; Erectile Dysfunction; Ethanolamines; Humans; Imidazoles; Male; Middle Aged; Muscle Relaxation; Muscle, Smooth, Vascular; Nebivolol; Nitric Oxide; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

The low pharmacological response to phosphodiesterase type 5 inhibitors represents an expression of higher endothelial damage in certain categories of patients with erectile dysfunction and high cardiovascular risk. The present study evaluated this objective in type 2 diabetic patients with erectile dysfunction, classified as "non responders" to Sildenafil.. Eighteen "responder" and twelve "non responder" type 2 diabetic patients were evaluated, relatively to different levels of endothelial damage, through the diagnostic use of a new immunophenotype of circulating endothelial progenitor cells (CD45neg/CD34pos/CD144pos) and endothelial microparticles (CD45neg/CD144pos/Annexin Vpos), recently developed and published by our group.. "Non responder" patients showed a significant higher severity [8.0±3.0 (International Index of Erectile Function-abbreviated version with 5 questions) vs 14.0±3.0] and duration (10.0±2.0 vs 7.0±2.0 years) of erectile dysfunction, higher level of penile arterial insufficiency (peak systolic velocity=13.0±16.0 vs 28.0±26.0cm/s; acceleration time=153±148 vs 125±128 mm/s) and finally a significant higher level of endothelial apoptosis [0.15±0.13 vs 0.05±.0.03% (serum concentrations of endothelial microparticles)] associated with higher serum concentrations of circulating late immunophenotype of endothelial progenitor cells (0.40±0.35 vs 0.12±.0.10%).. The results of this study corroborate the clinical value of the low clinical response to phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction in the patients with high cardiovascular risk profile, such as diabetics. In addition, the markers used in this study confirm their potential application in clinical practice as useful indicators of endothelial alteration. However, in the future we will have to assess a larger number of patients and for a longer period of observation in order to better understand the causal and temporal relations.

Topics: Aged; Apoptosis; Arteries; Cardiovascular Diseases; Cell-Derived Microparticles; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Resistance; Endothelium, Vascular; Flow Cytometry; Humans; Impotence, Vasculogenic; Italy; Male; Middle Aged; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

It is well established that the pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide (NO) generation. Many of the biological actions of NO are mediated by cGMP, which is rapidly degraded by phosphodiesterases. In this study, we evaluated the renoprotective effects of sildenafil (SIL), an inhibitor of phosphodiesterase-5, in type 2 diabetic rats.. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetes model, and Long-Evans Tokushima Otsuka rats, a non-diabetic control, were treated with either SIL (2.5 mg·kg(-1) in drinking water) or undosed water for 28 weeks, starting at 30 weeks of age.. Sildenafil treatment significantly decreased albuminuria, attenuated glomerular hyperfiltration and resulted in a decrease in glomerular hypertrophy, in addition to a reduced glomerulosclerosis score and a dramatic decrease in the number of glomerular and tubulointerstitial proliferating cell nuclear antigen-positive cells in OLETF rats. This was accompanied by a significant reduction in renal cortical mRNA levels of collagen types I and III. The increased mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 in the OLETF rats were significantly or partially attenuated by SIL treatment.. This study suggests that SIL attenuated diabetic nephropathy due to its potent antiproliferative effects and its regulatory effects on extracellular matrix. This latter effect is thought to be a result of its ability to affect the balance between MMPs and their inhibitors.

Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Cell Proliferation; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney; Kidney Function Tests; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Inbred OLETF; Sildenafil Citrate; Sulfones; Transforming Growth Factor beta1

Topics: Antioxidants; Carnitine; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Monocytes; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Antioxidants; Carnitine; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Erectile dysfunction (ED) in diabetes is related to autonomic neuropathy and endothelial dysfunction. We studied the relative importance of these factors in diabetic and non-diabetic men with ED and determined if they predict responses to treatment with sildenafil.. Thirty-three men, aged 35-65 years, with ED (20 diabetic, 13 non-diabetic), 15 of whom were sildenafil responders and 18 non-responders, were compared with 30 age and risk-matched control subjects (15 diabetic, 15 non-diabetic). Subjects with ED completed the International Index of Erectile Function (IIEF) questionnaire. Endothelial function was assessed by changes in brachio-radial and femoro-tibial arterial pulse-wave velocity (pulse-wave velocity) during reactive hyperaemia, expressed as percentage endothelium-dependent dilatation. Autonomic function was assessed by heart rate variation during expiration and inspiration (E/I ratio) and during the valsalva manoeuvre.. The respective changes in pulse-wave velocity, in the arm and leg [mean (sd)] were 0.71 (6.5)% and 3.5 (6.4)% in the impotent diabetic men, 0.7 (7.6)% and 2.4 (5.9)% in the non-diabetic impotent men, -0.68 (5.7)% and -1.31 (7.2)% in the non-impotent diabetic men and 7.7 (3.7)% and 7.6 (3.4)% in the control subjects. There was a significant interaction between ED and diabetic status such that there was significantly impaired vascular response in the diabetic group (both with and without ED) and in the non-diabetic group with ED compared with the non-diabetic control group (P = 0.01 and P = 0.001 for brachio-radial and femoro-tibial measures, respectively). The E/I ratios of the diabetic men were significantly lower than those of the control subjects [1.17 (0.14) vs. 1.33 (0.16), P < 0.02), but there were no differences in the measures of autonomic neuropathy between the groups with ED and those with normal erectile function. Amongst diabetic men, the initial IIEF scores (maximum score 30, low score indicates more severe ED) were significantly higher in sildenafil-responders than non-responders [16.3 (8.4), vs. 6.8 (7 1), P < 0.02]. The rate of sildenafil response was not significantly affected by the measures of endothelial or autonomic function.. ED in both diabetic and non-diabetic men is characterized by marked endothelial dysfunction in comparison with non-diabetic control subjects. Response to sildenafil is not predicted by either endothelial function or autonomic function, but in diabetic men appears to be related to the initial degree of erectile dysfunction.

Topics: Adult; Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Endothelium, Vascular; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Since Sildenafil (Viagra) has become available, there have been reports of death and cardiac risks associated with its use. As large doses of Sildenafil medication is often prescribed particularly in diabetic patients with erectile dysfunction (ED), our study was designed to evaluate the coronary flow reserve (CFR) and possible resulting cardiac risk specifically in diabetic men.. Because these men often suffer from clinically significant ischaemic heart problems without their knowledge and without symptoms, all of our patients were examined by treadmill ECG and CFR.. In 44 men (35 - 74 years) with type I and II diabetes also suffering from ED objectified by FCDS measurement of the penile vessels, a surprisingly high rate of objective cardiac problems were found, which were then verified by coronary angiography. These patients are at risk for ischaemic problems during Sildenafil-assisted intercourse and were excluded from further study. Interestingly, only 3 of theses 11 men would have been detected by conventional examinations. Patients free of coronary stenosis who received 50 mg Sildenafil (20 patients) showed no cardiac problems during treadmill exercise and CFR measurement.. Coronary flow reserve in diabetic men lies at the lower end of the normal range, but is not further decreased by Sildenafil. However, diabetics with ED frequently showed coronary artery stenosis that was not clinically symptomatic. Furthermore, conventional cardiological examinations often fail to detect these patients, although they are at ischaemic risk during medically assisted intercourse. Furthermore, although 5 of 20 men who received Sildenafil had an increase in penile blood flow without sexual stimulation, only 7 of 20 were responders to Sildenafil after take home medication. Thus, Sildenafil medication is not a suitable test medication for organic erectile dysfunction.

Topics: Adult; Aged; Blood Flow Velocity; Contraindications; Coronary Circulation; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Echocardiography, Doppler, Color; Exercise Test; Humans; Impotence, Vasculogenic; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Penis; Piperazines; Purines; Regional Blood Flow; Risk Assessment; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Brachial Artery; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate the cause of failure of sildenafil citrate (Viagra) to restore erections in patients with organic erectile dysfunction (ED) associated with type II diabetes mellitus (DM) and receiving oral antidiabetic drugs.. Diabetic ED patients (n = 120), aged 43-74 years, failing to respond at least three times to 100 mg Viagra were evaluated. After at least 2 weeks' treatment with oral testosterone undecanoate (Andriol), 100 mg Viagra was used before coitus. ED was assessed with the International Index of Erectile Function (IIEF). Serum total testosterone, prolactin, thyroid stimulating hormone, lipid profile and prostate-specific antigen (PSA) were determined by standard methods and prostate volume by digital rectal examination. Age-matched diabetic ED patients (n = 100) served as controls for baseline values.. Viagra non-responders had, at baseline, significantly lower testosterone and more depressed libido than controls. Andriol restored testosterone to normal levels and increased libido. In 84/120 (70%) Viagra non-responders, combined therapy with Andriol induced satisfactory erections, a significant increase in IIEF scale (question (Q) 3 from 2.0 +/- 0.2 to 3.7 +/- 0.3, Q4 from 1.9 +/- 0.1 to 3.4 +/- 0.2, Q12 from 1.0 +/- 0.1 to 4.2 +/- 0.4) and increased sexual contacts from 0.5 to 3-4 per month. No adverse events were noted, and PSA levels remained below 4 ng/ml.. Decreased testosterone levels in patients with ED and type II DM receiving oral antidiabetic against may be responsible for failure to respond to sildenafil citrate therapy. Combination with oral testosterone undecanoate restores sexual function in these patients.

Topics: Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Testosterone; Testosterone Congeners; Treatment Failure; Vasodilator Agents

Topics: Adult; Aged; Alprostadil; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Male; Middle Aged; Penis; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Male; Multicenter Studies as Topic; Phosphodiesterase Inhibitors; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Time Factors

To evaluate different dosages of vasoactive drug viagra in patients with erectile dysfunction suffering from diabetes mellitus (DM) type I and II.. Viagra in doses 25, 50 and 100 mg was given to 30 DM patients with different forms of erectile dysfunction.. The response was obtained in 70.3% of cases. The highest effect was achieved with the dose 100 mg (the response rate 68.5% of patients). The dose 50 mg was effective in 31.5%, 25 mg in 0% of patients. Most nonresponders had low testosterone levels in the blood.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Erectile Dysfunction; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Testosterone; Treatment Outcome

Impotence, a common problem especially among older men, can now be treated with Viagra, This oral pill, unlike previous approved treatments mostly involving local injections, does not directly cause penile erection, but increases response to sexual stimulation. It acts by enhancing the relaxant effects of nitric acid on smooth muscle, and thus increases blood flow to certain areas of the penis, leading to erection. It has been evaluated in many randomized trials and in all was more successful in inducing erection than placebos. The most common side-effects include headache, flushing and indigestion, but there have also been reports of fatalities. We describe a 75-year-old man who had an acute myocardial infraction in the past and who had maturity-onset diabetes and hypertension. In the week prior to admission he had a cardiac scan following a few weeks of exacerbation of anginal pain for which he had been taking nitrites. He took a Viagra pill without prescription or medical advice and 2 hours later, during intercourse with his wife, developed audible respiratory distress and lost consciousness. His wife started cardiac massage but not mouth-to-mouth breathing. The emergency team found ventricular fibrillation and gave 5 electrical shocks and amines and atropine. He remained unconscious, but his pulse returned and he was hospitalized. He then had several generalized convulsions treated with i.v. valium. 20 minutes after admission there was asystole and all attempts at resuscitation failed. Cardiovascular status must be considered prior to prescribing Viagra, and the associated risk evaluated.

Topics: Aged; Diabetes Mellitus, Type 2; Erectile Dysfunction; Fatal Outcome; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiratory Distress Syndrome; Sildenafil Citrate; Sulfones; Unconsciousness