Acute Sildenafil Research Articles

The determination of the protective role of sildenafil administration in rats with sepsis-in duced liver injury.

Sepsis is a complex syndrome which comes out after infection, characterized by activation of inflammation and infection and has a high morbidity and mortality. Sildenafil (SLD) is a selective Phosphodiesterase Type 5 (PDE-5) enzyme inhibitor and is used in the treatment of erectile dysfunction effectively all over the world. In this study, we investigated whether sildenafil had protective effect or not by studying the effect of sildenafil on reactive oxygen species and antioxidants in Cecal Ligation and Puncture (CLP) polymicrobial sepsis model in rat liver histopathologically and biochemically. Rats were divided into four groups: 1) 10 mg/kg SLD given CLP group; 2) 20 mg/kg SLD given CLP group; 3) CLP group; 4) SHAM operated group. CLP polymicrobial sepsis model was applied to the rats. All rats in our study were sacrificed by overdose general anesthetic after 16 hours (thiopental sodium, 50 mg/kg). Specimens of rat liver were analyzed histopathologically and biochemically. In the study, Superoxide Dismutase (SOD) and Glutathione (GSH) parameters were measured to indicate the antioxidant activity in liver during sepsis. To evaluate the oxidant activity, Myeloperoxidase (MPO) and Lipid Peroxidation (LPO) parameters were measured in liver tissue. SOD and MPO activities and GSH and LPO levels were high in CLP polymicrobial sepsis model when compared to SHAM group (P<0.05). In all sildenafil groups, GSH levels were high when compared to CLP group. In 20 mg/kg sildenafil given sepsis group, high GSH levels were observed according to SHAM group. In addition, while all sildenafil dose groups had a significant decrease versus CLP group in LPO levels (P<0.05), they had a significant increase in MPO activities. In 20 mg/kg sildenafil administrated rats, an improvement observed in biochemical parameters. In this study, SOD and MPO activities which were low in SHAM group increased in CLP polymicrobial sepsis model. When SLD administrated, MPO activity increased in both SHAM and CLP groups. In this study, GSH and LPO levels also increase in septic liver tissue. When SLD administrated to SHAM group, it increased protective GSH level and decreased detrimental LPO level. In histopathological examination, it was observed that 10 mg/kg sildenafil administration had a curative effect in liver tissue partly. In conclusion, it was shown that acute sildenafil administration decreased liver damage in septic rats dose-dependently in this study. In addition, it was observed that it corrected the broken oxidant-antioxidant balance. This might mediate the protective effect of sildenafil in liver. But we believe that new experimental and clinical studies should be in future to understand the protective effect of sildenafil in liver.

An acute oral administration of Sildenafil in asthenozoospermic patients improves sperm motility after density gradient centrifugation.

Objective:Investigate the possible effect of an acute sildenafil dose in asthenozoospermic patients.Methods:We ran this experimental, descriptive, prospective and non-blinded study in 32 patients diagnosed with asthenozoospermia according to the WHO criteria, after two consecutive semen analyses (samples 1 and 2), and we asked them to provide a new semen sample two weeks after the initial exams (sample 3). One hour prior to the semen collection, we gave the patients 100mg oral sildenafil. Samples 2 and 3 were allowed to liquefy and density gradients centrifugation was performed. We assessed sperm motility by Computer-assisted sperm analysis (CASA).Results:There were no significant differences between the samples obtained before (sample2) or after sildenafil administration (sample3). However, a single oral 100 mg sildenafil dose in asthenozoospermic patients increase the percentage of motile sperm recovered after density gradient centrifugation.Conclusions:An acute administration of sildenafil enhances sperm recovery after density gradient centrifugation in asthenozoospermic patients, and it may produce more available mobile sperm to perform intra uterine insemination or to improve the chances of success in this procedure. This approach may be used as an alternative strategy in assisted reproductive programs. Sildenafil was well tolerated and no patient was withdrawn from the study due to adverse events attributed to sildenafil.

Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

Background:Exercise intolerance is a common phenotype observed in patients with cystic fibrosis (CF). Treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has previously been shown to improve exercise capacity (VO2 peak) in other patient populations. Thus, the present study sought to determine the acute and subacute effects of sildenafil on exercise capacity in patients with CF.Methods:The present investigation utilized a randomized, double-blind, placebo-controlled, crossover study with an acute dose of either sildenafil (50 mg) or placebo (n = 13, age 25 ± 10), followed by a 4 week open-label extension with sildenafil (20 mg, TID; n = 15, age 23 ± 11). A comprehensive evaluation of pulmonary function and a maximal exercise test were each performed at every visit.Results:A significant increase in VO2 peak was observed after the acute sildenafil dose with no changes following placebo (77 ± 13 versus 72 ± 13% predicted; p = 0.033). In addition, after 4 weeks of treatment, patients showed a significant increase in exercise capacity (72 ± 12 versus 75 ± 12% predicted; p = 0.028) and exercise duration (409 ± 98 versus 427 ± 101 s; p = 0.014). A robust correlation (r = 0.656; p = 0.008) between baseline FEV1 (% predicted) and the change in exercise capacity following 4 weeks of treatment was identified.Conclusions:This proof-of-concept clinical trial demonstrates that sildenafil treatment can improve exercise capacity in patients with CF and that pulmonary function may play an important role in the effectiveness of treatment. Future investigations of sildenafil treatment in patients with CF are certainly warranted.

The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes

IntroductionFollowing the results of the EMPA-REG Outcome trial, we hypothesized that empagliflozin, a highly potent and specific sodium/glucose cotransporteur 2 inhibitor, could improve type 2 diabetes mellitus (T2DM)-associated erectile dysfunction (ED), a highly prevalent complication of T2DM, very often coexisting with cardiovascular complications and considered as a prognostic factor of cardiovascular disease in men with diabetes. AimTo investigate the effects of chronic treatment with empagliflozin on ED in a T2DM rat model in the presence or absence of sildenafil. MethodsMale Goto-Kakizaki (GK), a model of T2DM, and age-matched Wistar rats received placebo or empagliflozin treatment at 25.3 ± 0.9 mg/kg/d for 4 weeks. Then, the in vivo effect of empagliflozin on erectile function was assessed by electrical stimulation of the cavernous nerve at different frequencies under anesthesia in the presence or absence of acute intravenous injection of sildenafil. Endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from the rats were studied. Main Outcome MeasuresBody weight, food consumption, metabolic parameters, plasma inflammation biomarkers, and in vivo erectile responses elicited by electrical stimulation of the cavernous nerve in empagliflozin-treated and untreated GK rats and control Wistar rats were assessed and followed by concentration or frequency response curves to endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from these rats. ResultsChronic empagliflozin followed by acute sildenafil significantly improved erectile responses in adult GK rats (n = 12–15/group). Ratios of intracavernous pressure and area under the curve/mean arterial pressure during the electrical stimulation were significantly increased in empagliflozin-treated vs untreated GK rats. Nitrergic relaxations of cavernosal strips from GK rats were significantly increased with empagliflozin compared with placebo. Moreover, the effect of sildenafil on erectile function was not altered by empagliflozin treatment. Clinical ImplicationsEmpagliflozin may benefit T2DM patient with ED. Strengths & LimitationsThe mechanism(s) by which empagliflozin shows favorable effect on erectile function in GK rats needs to be further elucidated. ConclusionEmpagliflozin shows favorable effect on erectile function in diabetic GK rats mediated by an improvement of nitrergic relaxation of erectile tissue. Whether this favorable effect on ED in the experimental context of T2DM is due to better glycemic control or to another effect of empagliflozin deserves further investigation.Assaly R, Gorny D, Compagnie S, et al. The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes. J Sex Med 2018;15:1224–1234.

031 Low intensity-shockwave therapy (Li-ESWT) delivered by Aries® improves erectile function and decreases cavernosal fibrosis of spontaneously hypertensive rats (SHR)

Li-ESWT has been reported to improve erectile function in patients with vasculogenic ED, and convert PDE5i non-responders into responders. Erectile function of SHR, a validated rat model of hypertension associated ED, is partially improved by PDE5is. Here, we investigated whether Li-ESWT could affect erectile function with and without acute sildenafil in SHR. A pronounced accumulation of collagen in erectile tissue of SHR has been described, thus we also investigated the histological features of SHR erectile tissue after ESWT. 2 groups of male SHR (CTRL and ESWT; n=14/group) were treated twice/week for 6 weeks. Only in the ESWT group, shockwaves were delivered to the penis at the mid-shaft and base (Aries®, Dornier MedTech, Germany). Each session comprised 1000 shocks per site (total: 2000 shocks, EFD: 0.06 mJ/mm2). 4 weeks after the final session, erectile function was assessed by recording intracavernosal pressure (ICP) and mean arterial pressure (MAP) under electrical stimulation of the cavernous nerve (ES CN), first in absence then in presence of sildenafil (0.3mg/kg iv). Then rats were sacrificed, the corpora cavernosa were harvested and prepared for histological analysis. Cavernosal smooth muscle (SM)/collagen ratio was assessed by trichrome staining. Cavernosal microvasculature and nitrergic nerves were assessed by immunohistology against CD31 and nNOS.

Acute Sildenafil Treatment Improves Exercise Capacity in Patients with Cystic Fibrosis

BackgroundExercise capacity has been shown to predict quality of life, mortality, and risk for hospitalization in patients with Cystic Fibrosis (CF). Many patients with CF exhibit exercise intolerance, the mechanism of which has yet to be elucidated. Sildenafil, a phosphodiesterase type 5 inhibitor, increases blood flow and therefore may improve exercise capacity in patients with CF.PurposeThe purpose of this study was to determine whether an acute dose of sildenafil improves exercise capacity in patients with CF.Methods13 patients with CF (mean age = 25 ± 10 years) participated in a double blind, randomized, placebo controlled study. Exercise capacity utilizing the Godfrey Protocol on a cycle ergometer was assessed at baseline and 1 hour following treatment with either sildenafil (50 mg) or placebo.ResultsA significantly greater increase (p = 0.024) in VO2 peak was observed following sildenafil treatment (4.16 ± 1.54 ml/kg/FFM) compared to placebo (1.09 ± 1.31 ml/kg/FFM). The change in maximal heart rate during exercise was statistically (p = 0.007) greater following sildenafil treatment (6.07 ± 4.04 bpm) compared to placebo (−1.54 ± 6.06 bpm). The change in chronotropic index (CRI) was significantly (p = 0.006) higher following sildenafil treatment (0.08 ± 0.02) compared with placebo (0.04 ± 0.02).Conclusion/InterpretationThese findings suggest that an acute dose of sildenafil improves exercise capacity in patients with CF. In addition, treatment with sildenafil improved CRI. Future studies should focus on elucidating the mechanisms for improvement in exercise capacity and CRI as both are predictors of mortality.Support or Funding InformationSupported in part by the Medical College of Georgia's Medical Scholar Program and the Laboratory of Integrative Vascular and Exercise Physiology.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of sildenafil on the activity of some antidepressant drugs and electroconvulsive shock treatment in the forced swim test in mice

Sildenafil, a potent and selective inhibitor of phosphodiesterase type 5, is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. It is often taken by patients suffering from depression and receiving antidepressant drug treatment. However, its influence on the efficacy of antidepressant treatment was not sufficiently studied. Therefore, the aim of the present study was to investigate the influence of sildenafil on the anti-immobility action of several antidepressant drugs (i.e., sertraline, fluvoxamine, citalopram, maprotiline, trazodone, and agomelatine) as well as on antidepressant-like effect of electroconvulsive stimulations in the forced swim test in mice. The obtained results showed that acute sildenafil treatment enhanced the antidepressant-like activity of all of the studied drugs. The observed effects were not due to the increase in locomotor activity. The interactions between sildenafil and sertraline, maprotiline, and trazodone were pharmacodynamic in nature, as sildenafil did not affect concentrations of these drugs neither in serum nor in brain tissue. Increased concentrations of fluvoxamine, citalopram, and agomelatine in brain tissue evoked by sildenafil co-administration suggest that pharmacokinetic interactions between sildenafil and these drugs are very likely. Sildenafil injected acutely did not alter the antidepressant-like efficacy of electroconvulsive stimulations in mice, as assessed in the forced swim test. Interestingly, repeated (14 days) administration of sildenafil decreased the anti-immobility action of the electroconvulsive stimulations. In conclusion, the present study shows that sildenafil may alter the effectiveness of antidepressant treatment. Further studies are warranted to better characterize the influence of sildenafil on the activity of antidepressant drugs and electroconvulsive therapy.

Oxytocin is involved in the proconvulsant effects of Sildenafil: Possible role of CREB.

Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole-induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure.

Effect of Sildenafil on Pressure-Volume Loop Measures of Ventricular Function in Fontan Patients.

Sildenafil has been reported to improve exercise capacity in Fontan patients, but the physiologic mechanisms behind these findings are not completely understood. The objective of this study was to study the acute effect of sildenafil on pressure-volume loop (PVL) measures of ventricular function in Fontan patients. Patients after Fontan operation who were presenting for a clinically indicated catheterization were enrolled. Patients were randomized in a double-blinded fashion to receive placebo (n=9) or sildenafil (n=10) 30-90min prior to catheterization. PVLs were recorded using microconductance catheters at baseline and after infusion of dobutamine (10mcg/kg/min). The primary outcome was change in ventriculoarterial (VA) coupling. For the entire cohort, VA coupling trended toward improvement with dobutamine (1.4±0.4 to 1.8±0.9, p=0.07). End-systolic elastance showed improvement (2.6±0.9 to 3.8±1.4mmHgm(2)/ml, p<0.01) with dobutamine infusion. The cohorts had similar VA coupling at baseline (p=0.32), but the sildenafil cohort trended toward having less of an improvement in VA coupling with dobutamine stress (p=0.06). There were no differences between PVL measures of systolic or diastolic function between treatment groups, both at baseline and after dobutamine infusion. Patients with Fontan circulation had improved contractility and trended toward improvement in VA coupling with dobutamine stress. Acute sildenafil administration was not associated with improved PVL measurements of ventricular function in this population. These results suggest that clinical improvements seen with administration of sildenafil in Fontan patients are not associated with an acute improvement in ventricular function. www.clinicaltrials.gov ; Clinicaltrials.gov Identifier: NCT01815502.

Protective effect of exercise and sildenafil on acute stress and cognitive function

IntroductionThere are contradictory results about the effects of exercise and sildenafil on cognitive functions. AimTo investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions. MethodWistar rats (n=42) were divided as sedentary and exercise groups. A moderate-intensity swimming exercise was performed for 6weeks, 5days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis. ResultsIncreased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary-stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats. Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage.

MP52-07 EXPRESSION AND DISTRIBUTION OF CANNABINOID RECEPTORS IN THE HUMAN SEMINAL VESICLES

water-filled cage. Shockwaves were delivered by a calibrated probe yielding a controlled energy flux density of 0.09mJ/mm2 attached to a compact electrohydraulic unit with a focused shockwave source (Omnispec ED1000, Medispec Ltd, USA). Following a 4-week wash-out period, erectile function was assessed by electrical stimulation of the cavernous nerve in anesthetized rats and the effects of Li-ESWT alone or in combination with acute iv sildenafil (0.3mg/kg) were evaluated. Subsequently, ex vivo isometric tension studies were performed on CC from the same rats. RESULTS: Erectile function in GK rats was markedly impaired compared to age-matched Wistar rats and associated with altered endothelium-dependent, -independent and nitrergic mediated relaxations in CC. Either acute sildenafil or Li-ESWT significantly improved erectile responses in GK rats. Ratios of intracavernosal pressure and area under the curve /mean arterial pressure were significantly increased by 18% (p<0.001), 17% (p<0.05) and 32% (p<0.001), 23% (p<0.01), respectively versus untreated GK. This proerectile facilitator effect of Li-ESWT was not associated to improved endothelium-dependent, -independent or nitrergic reactivity of CC. The combination of Li-ESWT with sildenafil significantly potentiated the effect of Li-ESWT alone. CONCLUSIONS: Li-ESWT improves the erectile function of diabetic GK rats. Surprisingly, this effect is not mediated by a NO/ cGMP-dependent mechanism. Furthermore, this study shows additive effects when Li-ESWT is combined with a single dose of sildenafil.

No Synergic Effect of Sildenafil Administration on Exercise Capacity Improvement in a Fontan Patient with Regular Exercise Training

In Fontan patients, reduced exercise capacity due to diminished cardiac output is a common finding with important prognostic implications. Beneficial effects have been shown for sildenafil treatment and regular exercise, but data comparing both strategies is scarce. We report on a female patient with Fontan circulation who underwent repeated cardiopulmonary exercise tests with either placebo or a single dose of 50mg sildenafil before and after 6months of supervised aerobic and resistance exercise. At baseline, V O2peak was 29.1ml/min/kg, and a marked increase to 32.8ml/min/kg was observed after administration of sildenafil. After the training period, V O2peak was 34.5ml/kg/min in the placebo test, and no further increase by sildenafil was possible (33.7ml/kg/min). Similar results were observed for exercise capacity at the ventilatory anaerobic threshold. In summary, this Fontan patient showed that regular exercise might use up and probably Case Study Pressler et al.; CA, 2(4): 247-252, 2014; Article no. CA.2014.4.010 248 exceed the acute sildenafil effects on exercise capacity. Exercise should be considered as a primary treatment strategy within secondary prevention and rehabilitation after the Fontan procedure.

Effects of PDE type 5 inhibitors on left ventricular diastolic dysfunction in resistant hypertension.

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

Sildenafil Improves Small Artery Elasticity in Heart Transplant Recipients

Purpose Small artery elasticity (SAE) derived from radial artery pulse wave contour analysis is a measurement of endothelial function and a predictor of cardiovascular events in the general population. We have previously shown that SAE is reduced in heart transplant recipients (HTR) and is associated with cardiac allograft vasculopathy. In this study, we evaluated the effect of sildenafil on SAE in HTR. Methods and Materials We enrolled 11 stable HTR without recent history of rejection, infection, renal disease or CAV. SAE was measured prior to and one hour after administration of 50mg of oral sildenafil. Paired sample t-test was performed to compare SAE pre- and post-sildenafil. Results Median age was 62 yrs (range 44-72), 88% were male, median duration of transplant was 1 yr (range 1-3), and mean BMI was 26.5 ±3.72 kg/m2. 66% had prior ischemic cardiomyopathy. Mean baseline SAE was 3.7±1.1 ml/mmHgX10. One hour following administration of sildenafil, SAE increased significantly by 38% on average. The mean SAE after sildenafil was 5.2±2.3 ml/mmHgX10 (p= 0.032). [ figure 1 ] Conclusions Acute sildenafil treatment improves small artery elasticity in heart transplant recipients. Further studies are warranted to determine whether modification of endothelial function has clinical implications in heart transplant recipients.

Experimental Evidence for Sildenafil's Action in the Central Nervous System: Dopamine and Serotonin Changes in the Medial Preoptic Area and Nucleus Accumbens During Sexual Arousal

Sildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc). The aim of this study was to determine whether sildenafil administration alters dopaminergic and serotonergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal. An acute (2 days) or chronic (21 days) sildenafil regimen (1 mg/kg) was administered intraperitoneally to male rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact erection sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time. Tissue levels of DA and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as serotonin (5-HT) and its metabolite 5-HIAA, were measured in the mPOA and NAcc with high-performance liquid chromatography with electrochemical detector. Dopamine ([DOPAC+HVA]/DA) and serotonin (5-HIAA/5-HT) turnovers were also calculated as indices of neurotransmission. In nontrained males, acute and chronic sildenafil treatment increased DA and 5-HT turnover rates in the mPOA and NAcc. In trained rats, acute sildenafil also increased DA and 5-HT turnover rates in both structures, whereas chronic treatment enhanced 5-HT turnover rate only in the mPOA and DA turnover rate only in the NAcc. Our data confirm that sildenafil enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil-induced effects on serotonergic activity in these brain regions as well. Therefore, present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal.

Effect of Oral Sildenafil on Skin Postocclusive Reactive Hyperemia in Healthy Volunteers

Sildenafil is a type 5 phosphodiesterase inhibitor that has a theoretical ability to increase hyperemia following a short bout of ischemia. We tested if oral sildenafil increases skin PORH in healthy volunteers. We assessed forearm skin PORH (occlusion of blood flow for five minutes) in ten healthy volunteers 120minutes following the oral administration of 50 or 100mg of sildenafil. Cutaneous blood flow on the forearm was monitored using LDF. The PORH peak, expressed as a percentage of baseline, was clearly increased with 100mg sildenafil: 746% (95% CI 447-1044) versus 484% (95% CI 354-613) with 50mg sildenafil, and 468% (95% CI 347-588) without sildenafil (p=0.03 for 100mg versus 50mg and control). Oral sildenafil at 50mg increased the AUC of PORH on the forearm compared with control: 4568PU.sec (95% CI: 2252-6883) with 50mg sildenafil versus 1030 PU.sec (95% CI 737-1322) without sildenafil (p=0.006). Likewise, 100mg sildenafil increased the AUC (5271PU.sec (95% CI -81-10,623), albeit bordering on significance (p=0.07). Neither dose increased maximal LTH. Acute sildenafil administration at 50 and 100mg enhances skin hyperemia following a short bout of ischemia.

Res-Erection of Viagra as a Heart Drug

In 1998, the world was formally introduced to Viagra (sildenafil), the first oral agent to be approved in the United States for the treatment of erectile dysfunction. Developed by Pfizer chemists, sildenafil inhibited phosphodiesterase type 5 (PDE5), one of the 11-member superfamily of enzymes that hydrolyze cyclic nucleotide monophosphates and among the first discovered that was selective for cGMP. PDE5 had been identified more than 2 decades earlier, first as a protein that bound cGMP and later as one that hydrolyzed it (the binding function turning out to be a mechanism to regulate activity).1 Sildenafil induces vasorelaxation by blocking PDE5-cGMP hydrolysis, raising cGMP levels in smooth muscle to activate protein kinase G (also known as cGK). In platelets, this blunts thrombosis; together, the effects suggested a potential use for coronary vascular disease and hypertension. Pfizer initiated trials targeting coronary ischemia, but, although antianginal effects were disappointing, the study gave a whole new meaning to the term “side effect,” effectively hijacking sildenafil from cardiovascular development to a rather different indication. Article see p 8 There were still some cardiovascular studies performed, but essentially all were limited assessments of volunteer populations, mostly normal and at rest and some with cardiovascular disease; the results were interpreted to support safety for patients taking the drug. In particular, blood pressure changes were slight if present at all, and cardiac function appeared unaltered. Well into the mid 2000s, PDE5 was thought to be expressed in selective vascular beds, lung and corpus cavernosum being dominant, and to have a minor cardiovascular profile elsewhere, with a negligible role in the heart. Sildenafil reemergence as …

Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients with Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial.

Abstract 571 Background:Pulmonary hypertension (PH) is associated with increased mortality in patients with sickle cell disease (SCD). Methods:Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) is a multi-center (10 United States and United Kingdom Centers), placebo-controlled, double-blind 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (tricuspid regurgitant jet velocity [TRV] ≥2.7m/s) in adults and children (aged >12 years) with SCD. The primary endpoint was the six-minute walk distance (6MWD). The study was designed with a planned screening of approximately 1000 subjects, to enroll 132 subjects for inclusion in the nested Main Interventional Trial (MIT). In the screening trial, subjects were evaluated by history and physical examination, laboratory screening, transthoracic Doppler echocardiography and 6MWD. Randomized subjects were stratified by TRV (2.7-2.9 m/s and ≥3.0 m/s), and those in upper strata underwent a right heart catheterization (RHC). Preliminary Results:Of the 722 screened subjects, 150 (26%) had both a TRV ≥2.7 m/s AND 6MWD of 150-500 meters (m), qualifying for MIT enrollment. A total of 74 subjects (13%) were randomized into the MIT.The study was prematurely stopped due to a statistically significant increase in serious adverse events (SAEs) in the sildenafil arm after 33 subjects had completed the 16 week assessments and 74 subjects (37 sildenafil: 23 female, 47 ± 12 years, TRV 3.0 ± 0.4 m/s, 6MWD 378 ± 93 m; 37 placebo: 23 female, 44 ± 14 years, TRV 2.9 ± 0.3 m/s, 6MWD 381 ± 75 m) had been randomized in the MIT. To evaluate safety and efficacy, all 74 subjects were evaluated, with pre-defined primary and secondary endpoint analysis and imputation rules for missing data. Baseline gender, hemoglobin phenotype, TRV and 6MWD were similar between sildenafil and placebo (all p>0.05). There was a significant increase in SAEs in the sildenafil arm (46% vs. 22% of randomized subjects; p=0.048) but no significant difference in adverse events (AEs; 76% vs. 68%; p=0.607). Sickle cell anemia with crisis (hospitalization defining the SAE) accounted for the significant difference in SAEs (35% vs. 11%; p=0.025). In reference to AEs, patients on sildenafil tended to have more headache (27% vs. 14%; p=0.247) and more blurred vision (11% vs. 3%; p=0.358). No other SAEs or AEs by organ system or preferred term were significantly different (all p > 0.43). There were no AEs classified as life-threatening and there was one death in the placebo arm. To assess potential efficacy, all 33 subjects with TRV of ≥3.0 m/s underwent RHC and received a single test dose of 60 mg of sildenafil; data are currently availabel for 22 of those subjects. Although this dose of sildenafil acutely decreased mean pulmonary arterial pressure (p=0.01), and mean systemic arterial pressure (p<0.01), the change in pulmonary vascular resistance was not significant. There were no apparent safety issues with the acute sildenafil dosing (e.g. priapism). After 16 weeks of sildenafil, there was no difference in the change in TRV (adjusted mean change from baseline: sildenafil -0.10 ± 0.08 m/s, placebo -0.13 ± 0.8 m/s; p=0.7) or in 6MWD (adjusted mean change from baseline: sildenafil -17 ± 20.9 m, placebo +1.4 ± 21.8 m; p=0.47). On the Brief Pain Inventory (BPI), sildenafil subjects reported worsening pain during walking (p=0.07; p=0.17) and less enjoyment of life (p=0.09; p=0.04) vs. placebo at the interim visits (6 and 10 week, respectively). For subjects in the sildenafil group, no difference was detected in 6MWD for those experiencing a VOC vs. those without a VOC (adjusted mean 386 ± 15.9 m; 372 ± 11.7 m; p=0.39). Preliminary Conclusions:In conclusion, sildenafil significantly increased rates of VOCs requiring hospitalization vs. placebo. The premature study termination for safety concerns limited the sample size for efficacy assessments; however, further investigation may be warranted in a more select group of patients with optimized hydroxyurea and transfusion therapy. Based on the completed analyses, no relationship has been established between experiencing pain (via serious VOC) and 6MWD. Additional analyses will focus on determining whether pain (as measured by BPI) is correlated with change in 6MWD. Finally, these data suggest a potential role for the cyclic cGMP axis in the pathobiology of VOC and sickle cell disease related pain. Disclosures:Barst:Pfizer: Consultancy, Research Funding. Gibbs:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Girgis:Pfizer: Research Funding. Badesch:Pfizer: Consultancy, Research Funding.

Endothelium-mediated Modulation of Ergoreflex and Improvement in Exercise Ventilation by Acute Sildenafil in Heart Failure Patients

Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.

Testosterone Restores Diabetes‐Induced Erectile Dysfunction and Sildenafil Responsiveness in Two Distinct Animal Models of Chemical Diabetes

Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED). To investigate the role of hypogonadism on phosphodiesterase type 5 (PDE5) expression and sildenafil responsiveness in diabetes. Two different models of experimental diabetes were used: (i) alloxan-induced diabetic rabbit; and (ii) streptozotocin (STZ)-induced diabetic rat. In both experimental models, animals were separated into three groups: control, diabetic, diabetic supplemented with testosterone (T) enanthate. Rabbits were used for "in vitro" experiments. Conversely, each rats group was further subdivided: no further treatment or acute sildenafil dosing (25 mg/kg, 1 hour before "in vivo" electrical stimulation [ES]). Erectile capacity was evaluated either by "in vitro" contractility study (alloxan-induced diabetic rabbit) and "in vivo" evaluation of erectile response elicited by ES of cavernous nerve (STZ-induced diabetic rats). Also endothelial nitric oxide synthase, neural nitric oxide synthase (nNOS), and PDE5 protein (Western blot) and mRNA (quantitative real-time reverse transcriptase polymerase chain reaction [RT-PCR]) expression were measured in rat penile samples of each group. In both models, hypogonadism was observed, characterized by reduced T and atrophy of androgen-dependent accessory glands. T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to "in vitro" (acetylcholine, rabbit) or "in vivo" (ES, rat) relaxant stimuli, along with nNOS expression, which was reduced (P < 0.05) in STZ rats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both "in vitro" nitric oxide donor (NCX 4040) relaxant effect (rabbit) and "in vivo" ES-induced erection (rat). PDE5 was reduced in diabetic STZ rats (P < 0.05) and normalized by T. In STZ rats, sodium nitroprusside (SNP) intracavernous injection induced a more sustained erection than in control rats, which was no further enhanced by sildenafil. T substitution normalized both hyper-responsiveness to SNP and sildenafil efficacy. In two models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates sensitivity to relaxant stimuli and responsiveness to sildenafil.