Administration Of Phosphodiesterase-5 Inhibitors Research Articles

PDE5 inhibitors: breaking new grounds in the treatment of COVID-19.

Despite the ever-increasing occurrences of the coronavirus disease (COVID-19) cases around the world, very few medications have been validated in the clinical trials to combat COVID-19. Although several vaccines have been developed in the past quarter, the time elapsed between deployment and administration remains a major impediment. Repurposing of pre-approved drugs, such as phosphodiesterase 5 (PDE5) inhibitors, could be a game-changer while lessening the burden on the current healthcare system. Repurposing and developing phosphodiesterase 5 (PDE5) inhibitors could extrapolate their utility to combat the SARS-CoV-2 infection, and potentially aid in the management of the symptoms associated with its newer variants such as BF.7, BQ.1, BQ.1.1, XBB.1.5, and XBB.1.16. Administration of PDE5 inhibitors via the oral and intravenous route demonstrates other potential off-label benefits, including anti-apoptotic, anti-inflammatory, antioxidant, and immunomodulatory effects, by intercepting several pathways. These effects can not only be of clinical importance in mild-to-moderate, but also moderate-to-severe SARS-CoV-2 infections. This article explores the various mechanisms by which PDE5 inhibitors alleviates the symptoms associated with COVID-19 as well as well as highlights recent studies and findings. These benefits of PDE5 inhibitors make it a potential drug in the physicians' armamentarium in alleviating symptoms associated with SARS-CoV-2 infection. However, adequate clinical studies must be instituted to eliminate any untoward adverse events.

PDE5 inhibitors: breaking new grounds in the treatment of COVID-19.

Despite the ever-increasing occurrences of the coronavirus disease (COVID-19) cases around the world, very few medications have been validated in the clinical trials to combat COVID-19. Although several vaccines have been developed in the past quarter, the time elapsed between deployment and administration remains a major impediment. Repurposing of pre-approved drugs, such as phosphodiesterase 5 (PDE5) inhibitors, could be a game-changer while lessening the burden on the current healthcare system. Repurposing and developing phosphodiesterase 5 (PDE5) inhibitors could extrapolate their utility to combat the SARS-CoV-2 infection, and potentially aid in the management of the symptoms associated with its newer variants such as BF.7, BQ.1, BQ.1.1, XBB.1.5, and XBB.1.16. Administration of PDE5 inhibitors via the oral and intravenous route demonstrates other potential off-label benefits, including anti-apoptotic, anti-inflammatory, antioxidant, and immunomodulatory effects, by intercepting several pathways. These effects can not only be of clinical importance in mild-to-moderate, but also moderate-to-severe SARS-CoV-2 infections. This article explores the various mechanisms by which PDE5 inhibitors alleviates the symptoms associated with COVID-19 as well as well as highlights recent studies and findings. These benefits of PDE5 inhibitors make it a potential drug in the physicians' armamentarium in alleviating symptoms associated with SARS-CoV-2 infection. However, adequate clinical studies must be instituted to eliminate any untoward adverse events.

Phosphodiesterase-5 Inhibitor Use in Robot Assisted Radical Prostatectomy Patients Is Associated with Reduced Risk of Death: A Propensity Score Matched Analysis of 1,058 Patients.

We investigated whether the use of a phosphodiesterase-5 inhibitor (PDE5i) after robot assited radical prostatectomy has a survival benefit over non-use patients because there are controversial results on the association between PDE5i use and survival outcomes for prostate cancer patients in literature. We designed a retrospective, matched, large-sample cohort study of 5,545 patients who underwent robot assisted radical prostatectomy (RARP) during 2013-2021 in a single institute. The exclusion criteria was patients who were aged >70 years at surgery, American Society of Anesthesiologists (ASA) physical status classification grade 4 or 5, history of other malignancies, patients who started PDE5i 6 months after survery and patients with follow up period less than 24 months after surgery. Among the 1,843 included patients, 1,298 were PDE5i users, and 545 were PDE5i non-users. We performed propensity score matching (PSM) of PDE5i users (n=529) with non-users (n=529) by adjusting for the variables of age, Gleason grade group, pathological T stage, preoperative ASA physical status grade, and International Index of Erectile Function score. There were no significant difference in patient characteristics according to PSM. Kaplan-Meier curve revealed the difference of overall survival for PDE5i users and non-users (clustered log-rank test p<0.05). In a stratified Cox regression analysis, PDE5i use after RARP was associated with improved overall survival and reduced risk of death (hazard ratio 0.43; confidence interval 0.24-0.79; p=0.007). The limitation of this study was that the indication for the prescription of PDE5i was not given. PDE5i administration after RARP were associated with overall survival of patients with prostate cancer. A further randomized control trial may reveal whether routine use of PDE5i after prostatectomy can improve survival of prostate cancer patient.

Protective and therapeutic effects of sildenafil and tadalafil on aflatoxin B1-induced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has been classified as one of the most common forms of liver cancer occurring worldwide, and risk factors include hepatitis B & C virus, alcoholism, and dietary carcinogens like aflatoxin B1 (AFB1), which is produced by fungus Aspergillus flavus and Aspergillus parasiticus. Metabolism of AFB1 resulted into the formation of AFB1-exo-8, 9-epoxide which is largely responsible for HCC development. So far conventional cytotoxic chemotherapy has not provided much benefit in HCC, necessitating the need for newer treatment modalities. Recent reports suggest that phosphodiesterase-5 inhibitors (PDE5i) may have anticancer activity, but till date, the anticancer property of PDE5i (tadalafil & sildenafil) has not been evaluated in HCC. The present study was aimed to define the anticancer property of tadalafil and sildenafil against AFB1-induced HCC rats. Rats were randomly divided into five groups with five rats in each group. Except normal control group, rats of all other groups were fed with 5% alcohol via drinking water for 3weeks. After 3weeks, two successive dose of AFB1 (1mg/kg bw, ip) was administered on subsequent days followed by the administration of PDE5i (tadalafil & sildenafil, 10mg/kg bw) along with drinking water after 6weeks of treatment with AFB1 for 2weeks. An in-depth investigation into its mechanistic aspect revealed that development of HCC induced by aflatoxin B1, decreased the mRNA expression and activity of antioxidant enzyme SOD, GPx, catalase, GR and GST, and GSH content with a concomitant increase in the level of lipid peroxidation. Post-treatment with PDE5 inhibitor (tadalafil & sildenafil) restored the above parameters towards normal, and this result was more effective in case of sildenafil. Thus, results from the above studies suggest that PDE5 inhibitors may act as anticancer agents by preventing the development and progression of HCC by modulating the key parameters of antioxidant pathway.

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

Early administration of phosphodiesterase 5 inhibitors after induction of diabetes in a rat model may prevent erectile dysfunction.

The possible role of phosphodiesterase 5 inhibitors (PDE5Is) in prevention of negative effect of diabetes mellitus (DM) on erectile function is not well settled. To investigate the effect of early administration of vardenafil on erectile function, cavernosal structure, and genes expression in a rat model of DM. This experimental study was carried out atSuez Canal University's research laboratory. This study was conducted on a total of 60 adult male Albino Wistar rats, aged 60-80days and weighing an average of 200g. Rats were equally divided into six groups of 10 rats each: Group I (sham); Group II (DM with no treatment); Groups III, IV, V, and VI received vardenafil started at day 1, week 4, week 8, and week 12 after induction of DM, respectively. Functional study assessment of all groups was performed before euthanization, and then tissues were harvested for histopathological, ultrastructural, and molecular examinations. There was a significant difference of intracavernosal pressure between early (94±2.18) and late (40.5±1.94) treatment groups (p=0.011). Histopathological and ultrastructural changes of DM with no treatment and late treatment groups showed distorted cavernous architecture and extensive fibrosis. There was significant difference of smooth muscle to collagen ratio between early and late treatment groups (p=0.035). There was significant upregulation of nNOS(p=0.021) and iNOS (p=0.047) in early vs. late treatment group. The difference was insignificant in eNOS (p=0.386) or TGF-β1(p=0.149). Early treated rats with vardenafil had preserved erection and normal cavernosal structure, ultrastructure and gene expression of iNOS, nNOS, eNOS, and TGF-β1. Quantification of gene expression would improve our knowledge regarding cytokines expression and molecular background of DM-associated ED. Clinical application of this result may encourage early administration of PDE5I to prevent deleterious effects of DM on erectile function in newly diagnosed DM patients with probable uncontrolled blood glucose.

Two Birds with One Stone: Regular Use of PDE5 Inhibitors for Treating Male Patients with Erectile Dysfunction and Cardiovascular Diseases.

Patients with cardiovascular disease (CVD) frequently have erectile dysfunction (ED) because the two conditions have similar risk factors and potential mechanisms. The therapeutic effect of CVD is strongly dependent upon long-term management of the condition. Patients with CVD tend to have poor medication compliance, and the coexistence of ED often discourages patients with CVD from continuing their long-term CVD management, thus worsening CVD treatment compliance. The two major reasons for poor compliance are that (i) the adverse effects of cardiovascular medications on erectile function drive people to reduce the prescribed dosage or even stop taking the medications to obtain satisfactory sexual arousal and (ii) a worsening mental state due to ED reduces medication compliance. The regular administration of phosphodiesterase-5 inhibitors (PDE5is) guarantees that the prescribed medication dosages are easy to comply with and that they improve the mental status of patients by enhancing their erectile function, resulting in improved long-term management of CVD through medication compliance. PDE5is themselves also play a role in reducing cardiovascular events and improving the prognosis. We recommend prescribing PDE5is for ED and suggest that PDE5i administration is a promising strategy to improve the long-term management of patients with both ED and CVD.

Audiovisual Sexual Stimulation and RigiScan Test for the Diagnosis of Erectile Dysfunction.

Background:Currently available evaluation criteria for penile tumescence and rigidity have been fraught with controversy. In this study, we sought to establish normative Chinese evaluation criteria for penile tumescence and rigidity by utilizing audiovisual sexual stimulation and RigiScan™ test (AVSS-Rigiscan test) with the administration of phosphodiesterase-5 inhibitor.Methods:A total of 1169 patients (aged 18–67 years) complained of erectile dysfunction (ED) underwent AVSS-RigiScan test with the administration of phosphodiesterase-5 inhibitor. A total of 1078 patients whose final etiological diagnosis was accurate by means of history, endocrine, vascular, and neurological diagnosis, International Index of Erectile Function 5 questionnaire, and erection hardness score were included in the research. Logistic regression model and receiver operating characteristic curve analysis were performed to determine the cutoff value of the RigiScan™ data. Then, the multivariable logistic analysis was used in the selected variables.Results:A normal result is defined as one erection with basal rigidity over 60% sustained for at least 8.75 min, average event rigidity of tip at least 43.5% and base at least 50.5%, average maximum rigidity of tip at least 62.5% and base at least 67.5%, △tumescence (increase of tumescence or maximum−minimum tumescence) of tip at least 1.75 cm and base at least 1.95 cm, total tumescence time at least 29.75 min, and times of total tumescence at least once. Most importantly, basal rigidity over 60% sustained for at least 8.75 min, average event rigidity of tip at least 43.5%, and base at least 50.5% would be the new normative Chinese evaluation criteria for penile tumescence and rigidity. By multivariable logistic regression analysis, six significant RigiScan™ parameters including times of total tumescence, duration of erectile episodes over 60%, average event rigidity of tip, △tumescence of tip, average event rigidity of base, and △tumescence of base contribute to the risk model of ED. In logistic regression equation, predict value P < 0.303 was considered as psychogenic ED. The sensitivity and specificity of the AVSS-RigiScan test with the administration of phosphodiesterase-5 inhibitor in discriminating psychogenic from organic ED was 87.7% and 93.4%, respectively.Conclusions:This study suggests that AVSS-RigiScan test with oral phosphodiesterase-5 inhibitors can objectively assess penile tumescence and rigidity and seems to be a better modality in differentiating psychogenic from organic ED. However, due to the limited sample size, bias cannot be totally excluded.

Scrotal hemorrhage after testicular sperm aspiration may be associated with phosphodiesterase-5 inhibitor administration: a retrospective study

BackgroundScrotal hemorrhage after testicular sperm aspiration (TESA) is uncommon in clinical operation. Phosphodiesterase-5 inhibitors (PDE5i) are commonly given to men who have difficulty providing a sperm sample for assisted reproductive technique such as in vitro fertilization. In this study, we examine the incidence of scrotal hemorrhage after TESA in men who received a PDE5i.MethodsIn this retrospective study, 504 men with TESA operation in Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University were collected. Men in the drug group had taken orally PDE5i before TESA. Men in the control group only operated TESA. The testis volume, coagulation function were measured. Sonographic examination with Doppler imaging was performed when scrotal hemorrhage appeared.ResultsA total of 504 men with a mean age of 28.63 ± 4.22 years were included in the analysis. Of these, 428 did not receive a PDE5i prior to TESA and 76 received a PDE5i prior to TESA. Measures of coagulation function were not different between the groups. The incidence of hemorrhage was 0.0% in the control group and the drug group was 5.3%. The incidence of hemorrhage between two groups was different significantly (P = 0.000).ConclusionIn summary, the results of this study suggest that a PDE5i administration increases the risk of scrotal hemorrhage in men undergoing TESA, although the study design does not allow drawing a conclusion of cause and effect. Given the potential risk of scrotal hemorrhage after the ingestion of PDE5i, it may be wise not to administer it to men in whom a TESA may be performed.

The Effect of Oral Phosphodiesterase-5 Inhibitors on Sperm Parameters: A Meta-analysis and Systematic Review

To perform a systematic review and meta-analysis to evaluate the effect of phosphodiesterase-5 (PDE5) inhibitors on sperm parameters. A systematic literature search was performed. Mean value and its standard deviation (mean ± standard deviation) were used to perform quantitative analysis. Statistic heterogeneity scores were assessed with the standard Cochran Q test and I2 statistic. All statistical analyses were conducted by RevMan 5.3. Eleven studies embraced a total of 1317 participants and 19 subgroups or trials were included. Acute administration of PDE5 inhibitors had no effect on semen volume (mean value [MD] = 0.26; 95% confidence interval [CI]: 0.00-0.48) and sperm concentration (MD = 2.04; 95%CI: -2.95 to 7.04). However, the percentage of motile spermatozoa (MD = 7.05; 95%CI: 2.59-11.51), the percentage of total progressive motility (MD = 6.23; 95%CI: 2.43-10.04), and rapid progressive motility (MD = 3.11; 95%CI: 0.23-5.99) were increased after oral PDE5 inhibitors treatment. Interestingly, these significant changes were observed only in infertile men but not in normal patients (MD = 6.89, P < .001 vs MD = 0.67, P = .71; MD = 6.64, P = .001 vs MD = 2.11, P > .05; and MD = 3.89, P = .04 vs MD = 0.92, P = .59, respectively). The percentage of morphologically normal spermatozoa also increased in infertile men (MD = 12.15; 95%CI: 5.16-19.15). Limited evidence showed the linearity, abnormal forms of spermatozoa, as well as reproductive hormones (total testosterone, free testosterone, luteinizing hormone, and follicle-stimulating hormone) did not benefit from PDE5 inhibitors treatment. Oral PDE5 inhibitors treatment could modestly increase the sperm motility and morphology in infertile men.

Phosphodiesterase 5 Signals through HIPPO/TAZ Pathway in Maintaining Stemness of Prostate Cancer Cells

Cancer stemness is critical for the metastasis and relapse, however, the mechanism governing the maintenance of cancer stemness remains unknown. Herein, we have investigated the roles of phosphodiesterase 5 (PDE5) in stemness of prostate cancer cells. Both PDE5 and WW domain-containing transcription regulator protein 1 (TAZ), a major co-effector of the Hippo tumor suppressor pathway, are highly expressed in the PC3-derived cancer stem cells (PCSCs), and contribute to maintaining the stemness of PCSCs. Moreover, inhibition of PDE5 activity activates cGMP-dependent protein kinase G (PKG), PKG in turn activates MST/Lats kinases, leads to the cytosolic instability, and attenuates nucleus translocation of TAZ, resulting in inactivation of Hippo signaling. PDE5 inhibitor, vardenafil, not only attenuates the stemness of PCSCs but induces the trans-differentiation of them, these effects are abolished by knockdown of TAZ expression in PCSCs. Finally, in PC3 cells- and PCSCs-derived xenografts, administration of PDE5 inhibitor to the nude mice reverses the stem markers expression, whereas knockdown of TAZ in PC3 cells and PCSCs leads to the decreases in tumorigenesis and elimination of PDE5 inhibitors’ effects. Collectively, the present study demonstrates that inhibition of PDE5 activates hippo signaling to suppress TAZ in maintaining the stemness of PCSCs, and that PDE5 inhibitors could be an effective therapeutic intervention for metastasis and relapse of prostate cancer.

Scrotal Hemorrhage after Testicular Sperm Aspiration may be Associated with Phosphodiesterase-5 Inhibitor Administration

Scrotal Hemorrhage after Testicular Sperm Aspiration may be Associated with Phosphodiesterase-5 Inhibitor Administration

Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask): How do they work?

Phosphodiesterase 5 inhibitors (PDE5i) were developed while investigating novel treatments for coronary artery disease, but their andrological side effects shifted their indication toward the management of erectile dysfunction. Although PDE5i are now also indicated for pulmonary arterial hypertension and there are mounting preclinical and clinical evidences about their potentially beneficial cardiac effects, their use remains controversial and the involved mechanisms remain unclear. This review aimed to analyze the effects of PDE5i administration in various animal and humans models of cardiovascular diseases. Animal studies have shown that PDE5i have protective effects in several models of cardiac disease. In humans, some studies showed that PDE5i improves microvascular and endothelial dysfunction and exerts positive effects in different samples of cardiovascular (CV) impairment. In contrast, other studies found no benefit (and no harm) in heart failure with preserved ejection fraction. The discrepancies in these findings are likely related to the fact that the mechanisms targeted by PDE5i in human disease are still poorly understood and the target population not yet identified. The mechanisms of actions herein reviewed suggest that hypertrophy, microvascular impairment, and inflammation, should be variably present for PDE5i to work. All these conditions frequently coexist in diabetes. A gender responsiveness has also been recently proposed. Continuous PDE5 inhibition may exert cardioprotective effects, improving endothelial function and counteracting cardiac remodeling in some but not all conditions. A better patient selection could help to clarify the controversies on PDE5i use for CV disorders.

Therapy of endocrine disease. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis.

Diabetes mellitus (DM) is associated with endothelial dysfunction, reducing nitric oxide-dependent vasodilation, and increasing production of pro-inflammatory factors, leading to an increased risk of long-term cardiovascular disease. As the effects of phosphodiesterase 5 inhibitors (PDE5i) on endothelial function have not been systematically investigated, we conducted a meta-analysis of available randomized clinical trials (RCTs). A thorough search of the literature was carried out. Relevant studies were considered according to RCT study design, enrollment of men with type 2 DM, chronic administration of PDE5i, and evaluation of endothelial function through both hemodynamic and endothelial inflammation-related parameters. Fifteen studies fulfilled the eligibility criteria but only six RCTs met the inclusion criteria and were analyzed for 476 diabetic men, 239 randomized to Sildenafil, and 237 to placebo respectively. Four RCTs evaluated flow-mediated dilation (FMD), demonstrating a weighted mean increase of 2.19% (95% CI 0.48 to 3.90). This result showed a high heterogeneity (I(2): 98%). Thus, a further sub-group meta-analysis was performed and this analysis confirmed a significant, Sildenafil-related FMD improvement. Sildenafil improved endothelin 1 and high sensitivity C-reactive protein by ∼-0.94 pg/ml and -0.36 mg/l, respectively, not reaching statistical significance (P=0.69 and P=0.22 respectively). Finally, Sildenafil administration significantly reduced serum levels of interleukin 6 (IL6, -0.82 pg/ml; 95% CI -1.58 to -0.07). This meta-analysis suggests a beneficial effect of chronic PDE5i administration on endothelial function. Chronic Sildenafil administration seems to improve hemodynamic (FMD) and serum pro-inflammatory makers (IL6) in diabetic men. Larger studies are needed to confirm the effects of chronic PDE5i on endothelial function.

Evaluation of Current Errors Within the Administration of Phosphodiesterase-5 Inhibitors After More Than 10 Years of Use

To detect current errors within the administration of phosphodiesterase type 5 inhibitors (PDE5is) and evaluate and elucidate what percentage of patients could be recovered for oral therapy with different subtypes of PDE5is through a re-education program. Two hundred fifty patients remitted to the andrology unit were prospectively analyzed. Patients' chief complaint was erectile dysfunction despite treatment with PDE5i. The International Index of Erectile Function was used to measure erectile function. A structured interview was developed to evaluate the most frequent errors within the administration of PDE5is. A re-education program was offered to patients with incomplete or incorrect use of PDE5is according to the structured interview, classifying them into true nonresponders or false nonresponders. Finally, the percentage of patients who could be recovered for oral therapy with other PDE5is was analyzed. A total of 172 patients (69%) presented some error within drug administration. The most common error was not trying >1 PDE5i (41%). A re-education program was offered to these nonresponders, and 115 (66.9%) accepted. Up to 27 (23.5%) did not respond to the re-education program and were classified as true nonresponders, whereas 88 (76.5%) had a positive response to treatment and were thus included in the false nonresponder group. Two-thirds of patients remitted to our andrology unit and cataloged as nonresponders were in fact using PDE5i in suboptimal conditions. Offering patients more accurate information provided almost 76% with good results using PDE5is and could therefore be successfully treated with these drugs.

Acute cardiac and hemodynamic effects of sildenafil on resistant hypertension

Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)-inhibiting cGMP breakdown-reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses. Subjects (n = 26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined. Mean arterial pressure and total peripheral resistance decreased in all patients (84.17 ± 21.04 to 75 ± 17.21 mmHg; 1149 ± 459.7 to 1037 ± 340 dyn.s/cm(-5), respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25 ± 5.8 to 20 ± 4.4; IVRT: 104 ± 19.33 to 88 ± 15.22; E/e' septal: 9.7 ± 3.8 to 7.9 ± 2.9; E/e' lateral: 7.7 ± 3.4 to 6.4 ± 3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i. Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.

Treatment of pituitary prolactinoma reverses unresponsiveness to PDE5 inhibitor therapy in men with ED and SHPRL

Treatment of pituitary prolactinoma reverses unresponsiveness to PDE5 inhibitor therapy in men with ED and SHPRL

Title efficacy of phosphodiesterase 5 inhibitor on distant burn-induced muscle autophagy, microcirculation, and survival rate

Skeletal muscle wasting is an exacerbating factor in the prognosis of critically ill patients. Using a systemic burn injury model in mice, we have established a role of autophagy in the resulting muscle wasting that is distant from the burn trauma. We provide evidence that burn injury increases the autophagy turnover in the distal skeletal muscle by conventional postmortem tissue analyses and by a novel in vivo microscopic method using an autophagy reporter gene (tandem fluorescent LC3). The effect of tadalafil, a phosphodiesterase 5 inhibitor (PDE5I), on burn-induced skeletal muscle autophagy is documented and extends our published results that PDE5Is attenuates muscle degeneration in a muscular dystrophy model. We also designed a translational experiment to examine the impact of PDE5I on whole body and demonstrated that PDE5I administration lessened muscle atrophy, mitigated microcirculatory disturbance, and improved the survival rate after burn injury.

Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts

Diabetic patients are prone to metabolic perturbations that progressively contribute to structural, functional and proteomic alterations in the myocardium. Phosphodiesterase-5 (PDE-5) inhibitors exhibit cardioprotective effects against ischemic/reperfusion injury, however the effects of chronic administration of PDE-5 inhibitors, particularly under diabetic conditions, remain unknown. Hence, the present study was designed to identify novel protein targets related to long-acting PDE-5 inhibitor tadalafil-induced cardioprotection in diabetes. Using two-dimensional differential in-gel electrophoresis with 3 CyDye labeling and MALDI-TOF/TOF tandem mass spectrometry we identified alterations in the expressions of cardiac proteins in diabetic db/db mice treated with tadalafil. Tadalafil reversed the coordinated alterations of cytoskeletal/contractile proteins such as myosin light chain (MLY) 2 and 4, myosin heavy chain α and myosin-binding protein C which contributes to contractile dysfunction. The expression of intermediate filament protein vimentin and extra-cellular matrix proteins like cysteine and glycine rich protein-3 and collagen type VI α were upregulated in db/db mice indicating cardiac remodeling in diabetes. These detrimental proteomic alterations were reflected in cardiac function which were reversed in tadalafil treated mice. Tadalafil also enhanced antioxidant enzyme glutathione S-transferase Kappa-1 (GSKT-1) and downregulated redox regulatory chaperones like heat shock protein 8 (HSPA8), and 75kD glucose regulatory protein (75GRP). Furthermore, tadalafil treatment significantly attenuated GSSG/GSH ratio and improved the metabolic status of db/db mice. Chronic treatment with tadalafil in db/db mice modulates proteins involved in cytoskeletal rearrangement and redox signaling of the heart, which may explain the beneficial effects of PDE-5 inhibition in diabetes.

Abstract 17350: Altered PDE5 Targeting in Pathologic Hearts . Switching From NO-cGMP to ANP/BNP-cGMP

Background: cGMP degrading phosphodiesterase 5 (PDE5) resides at Z-band of adult cardiac myocyte and regulates cell physiology in a compartmentalized manner. Under physiological condition, it hydrolyzes cGMP derived from endothelial nitric oxide synthase (eNOS) but not from natriuretic peptide (NP). In hypertrophied hearts, however, PDE5 localization becomes diffuse though its expression and activity increases. We tested the hypothesis that PDE5 alters its targeting to NP-cGMP from eNOS -cGMP via diffusing its localization in pathological hearts where NP is up-regulated and eNOS is dys-regulated. Methods and Results: While acute administration of PDE5 inhibitor (sildenafil, 100µg/kg/min for 5min) does not affect ANP(10µg) -stimulated myocardial cGMP level in control mouse hearts, it significantly increased ANP-cGMP in hearts exposed to 1wk pressure overload (TAC). We further tested this hypothesis by examining the impact of PDE5 over-expression on TAC response of eNOS null hearts (eNOS KO). eNOS KO animals were crossed with cardiac myocyte specific PDE5 over-expressor (PDE5-TG), and animals were subject to 1week TAC at 2 months of age. eNOS KO alone showed ameliorated hypertrophic response, associated with reduced myocardial superoxide level, while PDE5 TG alone revealed exacerbated response, as reported. Importantly, PDE5 over-expressed eNOS KO hearts (PDE5TG-eNOSKO) revealed significantly exacerbated cardiac remodeling (chamber dilation and increase in heart weight) and impaired cardiac function compared to eNOS KO hearts, though myocardial superoxide level remained low. Cardiac fetal gene expression (ANP), calcineurin activity (RCAN-1 expression) and transient receptor potential cation channel 6(TRPC6) expression were all significantly higher in PDE5TG-eNOSKO than eNOS KO. Conclusion: These results suggest that increased NP-cGMP in cardiac hypertrophy/failure might be targeted by PDE5 via altered localization of the enzyme. Myocyte PDE5 regulation of NP-cGMP plays a pivotal role in the pathogenesis of remodeling independently of myocardial superoxide level. Sildenafil may enhance ANP/BNP activated cGMP pathway in heart failure patients to exert its cardiac protective effect.