Sildenafil Response Research Articles

The rs2682826 Polymorphism of the NOS1 Gene Is Associated with the Degree of Disability of Erectile Dysfunction.

Erectile dysfunction (ED) is a common male disorder, often associated with cardiovascular disease and ageing. The Sildenafil, a PDE5 inhibitor, can improve the erectile function by prolonging the nitric oxide (NO) downstream effect. NO is a molecule of pivotal importance in erection physiology and is mainly produced by neuronal nitric oxide synthase (nNOS) and endothelial NO synthase (eNOS). While it has been shown that eNOS and nNOS genetic polymorphisms could be associated with Sildenafil responsiveness in ED, no study so far has assessed whether nNOS polymorphisms and PDE5A polymorphism could be associated with increased risk to ED or with intensity of symptoms. A total of 119 ED patients and 114 controls were studied, with evaluation of the clinical disability by the International Index for Erectile Function instrument, plasma assessment of nitrite levels and genomic DNA analysis regarding the rs41279104 and rs2682826 polymorphisms of the NOS1 gene and the rs2389866, rs3733526 and rs13124532 polymorphisms of the PDE5A gene. We have found a significant association of the rs2682826 with lower IIEF scores in the clinical ED group. While this result should be confirmed in other populations, it may be helpful in establishing a genetic panel to better assess disease risk and prognosis on ED therapy.

Cavernous artery intima-media thickness predicts the response to sildenafil in erectile dysfunction patients as a morphological parameter.

While the intima-media thickness (IMT) of the cavernous artery was used for diagnosis for vascular erectile dysfunction (ED) with more accuracy than the peak systolic velocity, the role of the IMT in predicting treatment responses remained unexamined. A total of 136 patients with ED were enrolled. The baseline clinical and laboratory characteristics were collected. Penile Doppler ultrasonography (PDU) was performed on all patients by a blinded sonographer. Sildenafil was administrated to all patients with an adjusted dose of 50 or 100mg on demand over a period of 3months. A follow-up was conducted on all patients using the Erectile Hardness Score (EHS) questionnaire along with the visual and tactile version of the standardised EHS tool. The peak systolic velocity (PSV) and IMT were compared between sildenafil responders and sildenafil nonresponders, while receiver operator characteristic (ROC) curves were used to calculate the cut-off values and compare the test power respectively. There was no statistical difference from the baseline characteristics. The IMT of cavernous artery was more accurate than PSV to predict the sildenafil response (AUC=0.809, 0.626 respectively). IMT could predict sildenafil responders more accurately than PSV, and the cut-off value of the IMT of the cavernous artery was less than 0.22mm.

Nocturnal penile erections: A retrospective study of the role of RigiScan in predicting the response to sildenafil in erectile dysfunction patients

Sildenafil enhances the nitric oxide–cGMP pathway of erection, which is claimed to have a role in nocturnal penile tumescence and rigidity (NPTR). This study aimed to find whether RigiScan can predict the response to sildenafil among erectile dysfunction (ED) patients and to find which RigiScan parameter produces the best prediction. Medical records of 172 ED patients were revised regarding their full sexual history, standard andrology examination, NPTR monitoring by the RigiScan device, and the degree of response to sildenafil. Of 172 ED patients, 94 patients (54.7%) were sildenafil responders. All RigiScan parameters were higher in the sildenafil responder group. The RigiScan parameters with the most differentiating power between both sildenafil responders and non-responders were base rigidity (AUC 0.860) and then tip rigidity (AUC 0.831). The cut-off value of base and tip rigidity with the highest diagnostic accuracy was 42.5%. This finding was found to be more specific than the sensitivity in predicting a positive response to sildenafil (85.9% vs. 70.2% and 92.3% vs. 59.6%, for base and tip rigidity, respectively). Sildenafil response in ED cases can be predicted through NPTR monitoring using the RigiScan device and ED patients with RigiScan base or tip rigidity less than 42% are not expected to respond well to sildenafil.

Relationship between asymmetric dimethylarginine, nitrite and genetic polymorphisms: Impact on erectile dysfunction therapy

Sildenafil is the most used treatment of erectile dysfunction, however a large part of patients do not respond to therapy. This drug enhances nitric oxide (NO) signaling, and therefore factors that alter NO production may impact this drug responsiveness. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all NO synthases, and is metabolized by Dimethylarginine Dimethilaminohydrolase (DDAH) 1 and 2. Here we aimed to assess the relationship between plasma levels of ADMA and nitrite (marker of nitric oxide production) with Sildenafil responsiveness. We also studied genetic polymorphisms in DDAH1 and DDAH2 genes and their relation with biochemical and clinical data. Were included here 140 patients, divided in Clinical Erectile Dysfunction (CED) or Post-Prostatectomy Erectile Dysfunction (PPED) groups. Erectile function was evaluated before and after Sildenafil on-demand treatment using the International Index for Erectile Function Questionnaire. We have found that nitrite was associated with worse response to Sildenafil (r = − 0.25, P = 0.040). rs1554597 and rs18582 DDAH1 polymorphisms were associated with changes in ADMA levels in CED (B = − 0.23, P = 0.002; B = − 0.15, P = 0.017 for both variant genotypes, respectively). Finally, DDAH2 polymorphisms were associated with altered responsiveness to Sildenafil in PPED (B = +0.19, P = 0.027).

Influence of arginase polymorphisms and arginase levels/activity on the response to erectile dysfunction therapy with sildenafil.

Arginase 1 (ARG1) and arginase 2 (ARG2) compete with nitric oxide synthases for the substrate l-arginine. Here we aim to assess whether arginase 1 and 2 plasma levels, plasma arginase activity or genetic factors are associated with altered responsiveness to sildenafil. We studied 71 post-prostatectomy erectile dysfunction (ED) patients (PED group) and 72 clinical ED patients (CED). Patients responded to the International Index of Erectile Function questionnaire before and after the treatment. We found positive and negative correlations between plasma levels of arginase 1 and sildenafil responsiveness in the PED and CED groups, respectively. PED group also presented negative correlation between plasma arginase activity and sildenafil responsiveness. Sildenafil poor responders have shown higher plasma arginase activity in PED and higher arginase 1 levels on CED groups. In addition, variant genotypes for the rs2781659, rs2781667 and rs17599586 polymorphisms were associated with reduced arginase activity, as well as the GTTT ARG1 haplotype in CED group.

Clinical predictive factors of sildenafil response: a penile hemodynamic study.

Phosphodiestrase-5 inhibitors are an important line of treatment for erectile dysfunction (ED). To detect the clinical and hemodynamic predictors of sildenafil response, we conducted this study on 124 Egyptian men with ED. All patients were evaluated by thorough history and clinical assessment with measurement of the abridged international index of erectile function-5 (IIEF-5) score. All patients were then subjected to intracavernosal injection (ICI) of trimix and pharmaco-penile duplex ultrasonography (PPDU). Patients were then classified into sildenafil responders and non-responders after six consecutive doses of 100 mg sildenafil. On doing the binary logistic stepwise regression analysis, only ED duration, IIEF-5 score, and response to ICI were the significant independent predictors of sildenafil response. These three parameters together correctly predicted the sildenafil response by 81.5% (p value <0.001). With the receiver operator characteristic curve analysis, the cut-off value of ED duration was 2.5 years and it was 14 for the IIEF-5 score. These findings indicate that ED duration, the IIEF-5 score and response to ICI are more significant predictors of sildenafil response than the more expensive and time-consuming PPDU testing.

Comparing the effects of atorvastatin and vitamin E on endothelial function of sildenafil non‐responders (851.8)

ABSTRACT Endothelial dysfunction causes the failure of sildenafil response due to reduced nitric oxide (NO) . This study aimed to compare the biochemical and clinical effects of atorvastatin and vitamin E on endothelial function of sildenafil non‐responders with investigation to the underlying mechanisms.Methods: Sixty participants were randomly divided into three groups receiving atorvastatin 80 mg daily, or vitamin E 400 IU daily, or placebo capsules. Participants were examined both before and after six weeks for these biochemical tests; NO, glutathione peroxidase (GPO), interlukin 6 (IL‐6), testosterone, and endothelial nitric oxide synthase (eNOS) and for erectile function tests; international index of erectile function (IIEF ‐5) scores, rigiscan, and duplex l Results: in comparison to control group, the treated groups showed a significant increase in GPO, and a significant decrease in IL‐6. Atorvastatin only showed a significant increase in NO, eNOS, IIEF‐5 scores and rigiscan rigidity parameters. Other rigiscan parameters, testosterone and duplex ultrasound showed no difference in the three groups Conclusions: Atorvastatin improves endothelial function of sildenafil non‐responders by increasing NO level attributed to enhancing eNOS activity (main mechanism) added to antioxidant and anti‐inflammatory activities. Atorvastatin is a real promising drug for sildenafil non‐responders.

Impact of sildenafil on marital and sexual adjustment in patients and their wives after radiotherapy and short-term androgen suppression for prostate cancer: analysis of RTOG 0215.

The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives. RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives. There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09). Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response.

Randomized, Double‐Blinded, Placebo‐Controlled Crossover Trial of Treating Erectile Dysfunction with Sildenafil After Radiotherapy and Short‐Term Androgen Deprivation Therapy: Results of RTOG 0215

Erectile dysfunction (ED) may be the most commonly observed adverse event (AE) associated with the combination of radiation therapy (RT) and androgen deprivation therapy (ADT). A significant number of men are trying phosphodiesterase type 5 inhibitors (PDE5s) such as sildenafil to treat ED, yet sildenafil studies to date shed little light on the response to ED after ADT. The purpose of this trial was to evaluate sildenafil in the treatment of ED in prostate cancer patients previously treated with external beam RT and neoadjuvant and concurrent ADT. In this randomized, double-blinded crossover trial, eligible patients received RT/ADT for intermediate risk prostate cancer and currently had ED as defined by the International Index of Erectile Function (IIEF). Patients were randomized to 12 weeks of sildenafil or placebo followed by 1 week of no treatment then 12 weeks of the alternative. Treatment differences were evaluated using a marginal model for binary crossover data. The primary end point was improved erectile function, as measured by the IIEF. The study accrued 115 patients and 61 (55%) completed all three IIEF assessments. Sildenafil effect was significant (P = 0.009) with a difference in probabilities of erectile response of 0.17 (95% confidence interval: 0.06, 0.29), and 0.21 (0.06, 0.38) for patients receiving ≤ 120 days of ADT. However, as few as 21% of patients had a treatment-specific response, only improving during sildenafil but not during the placebo phase. This is the first controlled trial to suggest a positive sildenafil response for ED treatment in patients previously treated with RT/ADT, however, only a minority of patients responded to treatment. ADT duration may be associated with response and requires further study. The overall low response rate suggests the need for study of additional or preventative strategies for ED after RT/ADT for prostate cancer.

Predictors of Response to Sildenafil Citrate Following Radiation Therapy for Prostate Cancer

Phosphodiesterase type 5 inhibitor (PDE5) use is a treatment strategy for prostate cancer patients with post-radiation therapy (RT) erectile dysfunction (ED). To define the predictors of sildenafil response in men treated with RT for prostate cancer. International Index of Erectile Function (IIEF). Patients were enrolled prospectively if they met the following criteria: (i) either a three-dimensional conformal external beam (EBRT) or brachytherapy (BT) with or without androgen deprivation (AD) for prostate cancer; (ii) self-reported ability to have sexual intercourse prior to RT; (iii) experienced onset of ED following RT; (iv) candidates for sildenafil citrate use; (v) followed-up periodically; and (vi) completed the IIEF at least 12 months after RT. Failure to respond to sildenafil was defined as IIEF-erectile function (EF) domain score of <22. One hundred fifty-two patients met all the criteria: 110 in the EBRT group and 42 in the BT group. Mean age was 62 years. The mean follow-up was 38 months. Mean radiation dose for EBRT was 78 Gy and for BT was 101 Gy. Thirty-five patients received AD, 25% of EBRT, and 62% of BT patients. Sixty-one percent of the patients receiving AD had exposure only pre-RT, whereas 39% had pre- and post-RT AD exposure. The mean duration of AD was 4.6 months. Post-RT IIEF-EF domain score at >24 months was 17. Successful response to sildenafil occurred in 68% of men at 12 months after RT, 50% at 24 months, and 36% at 36 months. On multivariable analysis, predictors of failure to respond to sildenafil were: older age, longer time after RT, AD > 4 months duration, and RT dose > 85 Gy. Modality of radiation delivery was not predictive of sildenafil failure. A steady decrease in sildenafil response was seen with increasing duration after RT. Several factors were predictive of sildenafil failure.

A critical appraisal of erectile function in animal models of diabetes mellitus

The study of erectile function in diabetic animal models has revealed physiological alterations in neural, vascular, hormonal and endothelial function. The aims of this review are to further elucidate pathophysiological changes induced by diabetes mellitus and to introduce new concepts in the study of erectile dysfunction (ED) in animal models. The recognized pathophysiological mechanisms causing diabetic ED include oxidative stress and hormonal imbalance. The evolving treatments for ED include advanced glycosylated endproduct (AGE) inhibitors, phosphodiesterase type 5 inhibitors, protein kinase C (PKC) inhibitors, hormone replacement, and gene transfer techniques. Our current understanding of how these multiple pathophysiological mechanisms contribute to ED is discussed. In this review, diabetic animal model studies have documented that oxidative stress is a pre-eminent pathophysiological mechanism and several anti-oxidants, such as alpha-lipoic acid, vitamin E, sodium selenate, melatonin, and ascorbic acid, reverse both neurogenic and endothelial dysfunction in diabetic models. Further, the peroxynitrite decomposition catalyst - FeTMPyP, PKC beta selective inhibitor - LY333531, I kappaB kinase 2 inhibitor - AS602868, AGE inhibitors - aminoguanidine and ALT-711 show promise by exploring different cellular mechanisms in treating diabetic problems. A number of vectors have been used to insert genes to increase the expression of nitric oxide synthase, superoxide dismutase, maxi-K channel (hSlo), neurotrophin-3, and vasoactive intestinal polypeptide for the treatment of erectile function. Further investigation of the hormonal treatment of diabetes associated with hypogonadism may improve sildenafil responsiveness in diabetic patients. We are optimistic that novel prevention and treatment strategies for diabetic ED are on the horizon.

Atorvastatin Ameliorates Sildenafil-Induced Penile Erections in Experimental Diabetes by Inhibiting Diabetes-Induced RhoA/Rho-Kinase Signaling Hyperactivation

One of the proposed mechanisms responsible for diabetes-related erectile dysfunction (ED) is overactivity of RhoA/ROCK signaling, as seen in experimental models of chemical diabetes. Because statins may interfere with RhoA/Rho-kinase (ROCK) signaling through the reduction of geranyl-geranyl pyrophosphate (GGPP), required for RhoA activation, we investigated whether atorvastatin ameliorated diabetes-related ED. Streptozotocin-induced (8 weeks) diabetic rats and alloxan-induced (8 weeks) diabetic rabbits received atorvastatin (5 mg/kg daily) for the last 2 weeks. In vitro contractility studies were conducted in the rabbit model. In the rat model, sildenafil effect on electrical stimulation (ES)-induced erection was investigated. Atorvastatin action was also analyzed using human fetal penile smooth muscle cells (hfPSMCs) exposed to low (5 mM), high (22 mM), and very high (40 mM) glucose. Atorvastatin effect on hyperglycemia-induced RhoA/ROCK signaling was evaluated using the ROCK inhibitor Y-27632 in both animal models and by analyzing functional effects downstream to RhoA activation in hfPSMCs. In both diabetic models, atorvastatin did not affect glycemia, lipid plasma levels, and the hypogonadal state. In diabetic rats, atorvastatin ameliorated the erectile response to the ES of the cavernous nerve and normalized sildenafil effect on erectile function, strongly decreased by diabetes. In penile tissue from diabetic animals, atorvastatin completely restored the diabetes-induced hypersensitivity to Y-27632 and prevented RhoA membrane translocation/activation. In hfPSMCs, high glucose significantly increased not only membrane RhoA expression, but also ROCK activity (increased phosphorylation of the ROCK substrate myosin phosphatase target subunit 1) and several RhoA-dependent functions such as proliferation, migration, and smooth muscle-related gene expression. Atorvastatin restored all the high-glucose-induced effects, an action specifically reverted by GGPP. Atorvastatin improves diabetes-related ED and restores sildenafil responsiveness, most probably by inhibiting RhoA/ROCK signaling, which underlies several high-glucose-induced derangements in penile smooth muscle cell commitment.

Efficacy and limits of sildenafil citrate in patients with arterial erectile dysfunction: role of peripheral arterial disease and cardiovascular comorbidities

To evaluate whether the response to sildenafil administration in patients with arterial erectile dysfunction (ED) was related to their peak systolic velocity (PSV), peripheral atherosclerosis, cardiovascular risk factors (RF) and/or comorbidities at low cardiovascular risk. We enrolled 97 patients with 1-2 RF and comorbidities, combined with arterial ED alone (group A, n = 27), ED plus atherosclerotic carotid artery (group B, n = 23), ED plus lower limb artery abnormalities (group C, n = 25), and ED plus carotid and lower limb artery abnormalities (group D, n = 22). Sildenafil efficacy (100 mg twice a week for 12 weeks) was also examined in patients with =or>3 RF, peripheral atherosclerosis and no cardiovascular comorbidities (group E, n = 20). Median PSV was 24.1, 21.0, 19.3, 14.5 and 17.5 cm/s in groups A, B, C, D and E, respectively. Sildenafil response was higher in group A patients (77.8%), intermediate in groups B and C (65.2% and 56%) and lowest in groups D (45.4%) and E (50%), and the response in latter two groups was significantly lower than in the other three groups. In addition, sildenafil response was negatively influenced by: =or>3 RF, peripheral atherosclerosis and no systemic comorbidity, or presence of 1-2 RF associated with extended atherosclerosis and comorbidities. The number of comorbidities was positively related to atherosclerosis localization or extension (25, 35, 38 and 47 in groups A, B, C and D, respectively). Low sildenafil efficacy in patients with arterial ED was associated with extended atherosclerosis. These patients should undergo extensive ultrasonography and a full cardiovascular examination.

PREDICTORS OF RESPONSE TO SILDENAFIL CITRATE FOLLOWING RADIATION THERAPY FOR PROSTATE CANCER

Introduction. Phosphodiesterase type 5 inhibitor (PDE5) use is a treatment strategy for prostate cancer patients with post-radiation therapy (RT) erectile dysfunction (ED). Aim. To define the predictors of sildenafil response in men treated with RT for prostate cancer. Main Outcome Measures. International Index of Erectile Function (IIEF). Methods. Patients were enrolled prospectively if they met the following criteria: (i) either a three-dimensional conformal external beam (EBRT) or brachytherapy (BT) with or without androgen deprivation (AD) for prostate cancer; (ii) self-reported ability to have sexual intercourse prior to RT; (iii) experienced onset of ED following RT; (iv) candidates for sildenafil citrate use; (v) followed-up periodically; and (vi) completed the IIEF at least 12 months after RT. Failure to respond to sildenafil was defined as IIEF-erectile function (EF) domain score of 24 months was 17. Successful response to sildenafil occurred in 68% of men at 12 months after RT, 50% at 24 months, and 36% at 36 months. Onmultivariable analysis, predictors of failure to respond to sildenafil were: older age, longer time after RT, AD > 4 months duration, and RT dose > 85 Gy. Modality of radiation delivery was not predictive of sildenafil failure. Conclusions. A steady decrease in sildenafil response was seen with increasing duration after RT. Several factors were predictive of sildenafil failure. Teloken PE, Parker M, Mohideen N, and Mulhall JP. Predictors of response to sildenafil citrate following radiation therapy for prostate cancer. J Sex Med 2009;6:1135–1140.

Effects of pioglitazone on erectile dysfunction in sildenafil poor-responders: a randomized, controlled study

The effects of pioglitazone on sildenafil responsiveness in men with erectile dysfunction(ED) and a history of poor response to sildenafil were assessed. In a double-blinded study,38 men aged 47 +/- 1.5 years with moderate-to severe ED and poor response to sildenafil were randomly assigned to take a premedication of pioglitazone 30 mg (n=19) or placebo (n=19) once daily for 9 weeks along with on-demand use of sildenafil during the last month of pioglitazone treatment.Erectile function (EF) scores, assessed by EF domain of International Index of Erectile Function (IIEF), along with responses to Global Assessment Questions (GAQs) were major outcome measures. Serum levels of total testosterone (T),dehydroepiandrosterone sulfate (DHEAS), glucose,lipid profile and liver function test were minor outcome measures. Pioglitazone significantly improved major outcome measures compared with placebo. The decrease from baseline of total cholesterol level was more in pioglitazone than in placebo-treated groups. In 84% (32 out of 38) of the sildenafil poor-responders, at least one of the associated risk factors of ED was found. There was undiagnosed hypercholesterolemia in 34% of the subjects. Serum levels of T, DHEAS, glucose and other parameters remained unchanged in both groups. The intervention was well tolerated. Pioglitazone increased sildenafil response to improve ED of men with prior sildenafil failure and seems to be safe based on the present preliminary study. This improvement is likely regardless of fasting glucose and sex hormones levels.

Sildenafil (Viagra) Evokes Retinal Arteriolar Dilation: Dual Pathways via NOS Activation and Phosphodiesterase Inhibition

Sildenafil (Viagra; Pfizer, New York, NY), a selective phosphodiesterase type-5 (PDE5) inhibitor, is widely used to treat impotence by improving penile blood flow via elevation of cGMP. However, its effect on ocular circulation is controversial and whether retinal arterioles are responsive to this drug remains unclear. In this study, the direct reaction of retinal arterioles to sildenafil was examined and the signaling pathway underlying this vasomotor activity was probed. Retinal arterioles from porcine eyes were isolated, cannulated, and pressurized without flow. Diameter changes in response to sildenafil were recorded using videomicroscopic techniques. Retinal arterioles (67 +/- 2 microm) dilated dose dependently to sildenafil (1 ng/mL to 1 microg/mL). This dilation was inhibited by the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the guanylyl cyclase inhibitor 1H- [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), the extracellular signal-regulated kinase (ERK) pathway inhibitor PD98059, the nonselective potassium channel blocker tetraethylammonium (TEA), and the selective adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel blocker glibenclamide. The vasodilation elicited by the NO donor S-nitroso-N-acetylpenicillamine (SNAP) was inhibited by ODQ and TEA but was insensitive to PD98059. In the presence of L-NAME, the addition of SNAP (1 microM) produced modest vasodilation and the inhibited sildenafil response was subsequently restored. The restored dilation was insensitive to PD98059 but was blocked by TEA. Activation of NO synthase, through ERK signaling, leading to NO production and subsequent guanylyl cyclase activation and K(ATP) channel opening is the major vasodilatory pathway for sildenafil in retinal arterioles. Moreover, the elevated cGMP, from endogenous or exogenous NO, plays a permissive role for sildenafil to exert vasodilation through inhibition of the PDE5 pathway independent of ERK signaling.

Atorvastatin But Not Elocalcitol Increases Sildenafil Responsiveness in Spontaneously Hypertensive Rats by Regulating the RhoA/ROCK Pathway

Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil-containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose-dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, alpha-smooth muscle actin, SM22alpha, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR, likely by interfering with RhoA/ROCK signaling within the penis.

Analysis of the Impact of Androgen Deprivation Therapy on Sildenafil Citrate Response Following Radiation Therapy for Prostate Cancer

Radiation therapy is a widely accepted strategy for prostate cancer. Erectile dysfunction is a common complication of radiation therapy. Adjuvant androgen deprivation was shown to prolong survival in select patients. There is controversy regarding the impact of androgen deprivation on erectile function. We defined the impact of androgen deprivation on the sildenafil response in patients with erectile dysfunction following radiation therapy. Patients were enrolled prospectively if they underwent radiation therapy in the form of 3-dimensional conformal external beam or brachytherapy with or without androgen deprivation, reported functional erections before radiation therapy, experienced the onset of erectile dysfunction following the completion of radiation therapy, had comprehensive erectile dysfunction evaluation, including a thorough history and physical examination, attempted sildenafil periodically and completed the International Index of Erectile Function on at least 2 occasions throughout the first 3 years following the completion of radiation therapy. A total of 152 patients were enrolled. Mean age +/- SD was 62 +/- 14 years. No significant difference existed in age or radiation dose between patients with and without androgen deprivation exposure. Mean androgen deprivation duration was 3.8 +/- 1.8 months. For patients with conformal external beam and brachytherapy the sildenafil response, mean erectile function domain score and percent who experienced erectile function domain normalization at each time point were lower in those with vs without androgen deprivation. Androgen deprivation seems to exert a deleterious effect on erectile function in men undergoing radiation therapy for prostate cancer. This was observed in men treated with conformal external beam and brachytherapy at short-term, medium term and long-term followup.

The Correlation Between Erectile Function and Patient Satisfaction

The International Index of Erectile Function (IIEF) has become the gold standard inventory for the assessment of sexual function in drug trials and in clinical research. Normalization of the erectile function domain (EFD) score, an end of treatment score of 26 or higher, is an end-point that is currently being used routinely in drug trials. It has been our experience that some men with scores less that 26 on a sexual pharmaceutical are content with their sexual function. We undertook this study to define what proportion of men with EFD scores <26 are satisfied with their therapeutic response. 100 consecutive patients who had presented to a sexual health clinic and who had used sildenafil citrate on at least 4 occasions completed the IIEF pertaining to their sildenafil response. They were also asked questions, pertaining to their ability to have sexual intercourse (Q1), their satisfaction with their erectogenic medication (Q2), the ability of the medication to improve erectile rigidity (Q3), and the ability of the medication to improve their ability to have sexual intercourse (Q4). Patients were subcategorized into 4 groups based on treatment IIEF scores (>/=26, 22-25, 18-21, and 11-17). The IIEF scores were compared to the responses to the global assessment questions. The mean patient age was 58 +/- 22 years. For Q1 and Q2, for each subcategory, there was a significant difference in the percentage of men answering definitely, somewhat, or not at all. In the group with EFD scores 22-25, 67% agreed at least somewhat with Q1 and 66% with Q2. In this group 84% and 78% responded in the affirmative to Q3 and Q4, respectively. No patient with an EFD score <22 definitely agreed with Q1 or Q2. These data indicate that a significant proportion of patients with EFD scores 21-25 can have sexual relations that are satisfactory and that they are satisfied with their erectogenic medication.

The association between intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms of ecNOS gene and sildenafil responsiveness in patients with erectile dysfunction

The objective of the study was to determine the association between intron 4 variable number of tandem repeats (VNTR), E298A and IVF 23+10 G/T polymorphisms of ec-NOS gene and sildenafil responsiveness in patients with erectile dysfunction (ED). Ninety-six patients who were evaluated for ED between November 2003 and June 2004 and 167 healthy individuals representing the normal population as controls were included in the present study. The patients were evaluated by medical history, five-item version of International Index of Erectile Function, serum glucose, testosterone levels and lipid profiles. Sixty-seven patients received four consecutive doses of sildenafil from 25 to 100 mg according to the response. The ec-NOS gene intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms were evaluated in the isolated DNA blood samples obtained from the patient group with ED (n=96), from the group received sildenafil (n=67) and from the healthy group (n=167). Genotype distributions of ec-NOS gene intron 4, E298A and IVF 23+10 G/T polymorphisms in the patient group were similar to those in the healthy group. The frequency of the ec-NOS gene intron 4 genotype were found as bb=41.7%, ab=50% and aa=8.3% in the sildenafil responders and bb=93.5% and ba=6.5% in the sildenafil non-responders. This finding was statistically significant. Statistical analysis of ec-NOS gene E298A and IVF 23+10 G/T polymorphisms did not reveal any significant difference between sildenafil responders and non-responders. These findings may indicate that 'a' allele of ec-NOS gene intron 4 VNTR polymorphism associates with a better sildenafil response.