Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Phosphodiesterase 5A regulates the vomeronasal pump in mice.

The vomeronasal organ (VNO) is a specialized chemoreceptive structure in many vertebrates that detects chemical stimuli, mostly pheromones, which often elicit innate behaviors such as mating and aggression. Previous studies in rodents have demonstrated that chemical stimuli are actively transported to the VNO via a blood vessel-based pumping mechanism, and this pumping mechanism is necessary for vomeronasal stimulation in behaving animals. However, the molecular mechanisms that regulate the vomeronasal pump remain mostly unknown. In this study, we observed a high level of expression of phosphodiesterase 5A (PDE5A) in the vomeronasal blood vessel of mice. We provided evidence to support the potential role of PDE5A in vomeronasal pump regulation. Local application of PDE5A inhibitors-sildenafil or tadalafil-to the vomeronasal organ (VNO) reduced stimulus delivery into the VNO, decreased the pheromone-induced activity of vomeronasal sensory neurons, and attenuated male-male aggressive behaviors. PDE5A is well known to play a role in regulating blood vessel tone in several organs. Our study advances our understanding of the molecular regulation of the vomeronasal pump.

Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions.

Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced nitric oxide (NO)-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased reactive oxygen species levels that inactive NO, and testosterone deficiency that leads to endothelial nitric oxide synthase downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. SIGNIFICANCE STATEMENT: This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, hydroxyurea, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants.

Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors- Towards Wound Healing.

Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed in vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.

Possible retinotoxicity of long-term vardenafil treatment.

Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.

Maternal tadalafil treatment does not increase uterine artery blood flow or oxygen delivery in the pregnant ewe.

Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .

Induction of cGMP-mediated migraine attacks is independent of CGRP receptor activation.

BACKGROUND: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration. RESULTS: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo (p = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p = 0.026) and a simultaneous increase in heart rate (AUC, p < 0.001) during the first hour after administration compared to placebo. CONCLUSION: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier NCT05889455.

Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.

Design, synthesis, and biological evaluation of some new 2-phenyl-3,6-pyridazinedione derivatives as PDE-5 inhibitors.

Various 2-phenyl-3,6-pyridazinedione derivatives 4a-j, 5a-c, 6a,b, 7a-c, 8, 9, 10a-d, and 11a-d, were effectivelysynthesized, and tested for their potential inhibition of phosphodiesterase enzyme at 10 µM. Then fourteen compounds exhibiting the highest inhibition 4b, 4d, 4e, 4g, 4h, 4i, 5a, 6a,b, 7c, 10a,b, 11a, and 11d were selected for screening their PDE-5 inhibition, where compounds 4b,g,h, and 11a revealed promising PDE-5 inhibition having IC50 values = 25, 53, 22, and 42 nM, respectively in comparison with Sildenafil (IC50 = 16 nM). Additionally, these four most active compounds were safe to normal fibroblast cell line WI-38. Moreover, 4f, 4h, 4j, 10d, and 11d had almost the same anti-proliferative effect against the aortic cell line as Sildenafil. Furthermore, molecular docking illustrated that the binding of the target compounds with the key amino acids in the binding site of PDE-5 (PDB 2H42) was like to that of the cocrystallized ligand Sildenafil. Additionally, molecular dynamics simulation for the most active compound 4h revealed high stability of the 4h -PDE5 complex explaining its promising activity as a PDE-5 inhibitor. Therefore, the 2-phenyl-3,6-pyridazinedione scaffold can be considered an important core for designing more promising PDE-5 inhibitors.

Inflammation in cerebral ischemia reperfusion improved by avanafil via nod-like receptor protein-3 inflammasome: an experimental study in rats.

OBJECTIVE: The aim of study was to investigate the effect of avanafil, a second-generation phosphodiesterase-5 (PDE5) inhibitor, on cerebral ischemia reperfusion (CI/R) model. METHODS: 32 male albino Wistar rats were used. Four groups were constituted, as I: the healthy (sham), II: the CI/R group, III: the CI/R +I 10 mg/kg avanafil group, and IV: the CI/R + 20 mg/kg avanafil group. Avanafil was administered twice via oral gavage, first shortly after ischemia reperfusion and once more after 12 h. The rats were euthanized after 24 h. Histopathological and Real Time PCR analyzes were performed on cerebral tissues. RESULTS: IL-1ß, NLRP3 and TNF-α mRNA expressions were statistically higher in the CI/R group when compared to healthy (sham) group. Conversely, the IL-1ß, NLRP3, and TNF-α mRNA expressions were significantly decreased in both of the avanafil-treated groups when compared to CI/R group. Histopathological results showed that both doses of avanafil also decreased cellular damage in cerebral tissue that occurred after CI/R. CONCLUSION: Avanafil, was found to have ameliorated inflammatory response and cellular injury caused by CI/R. The mRNA expression of IL-1ß, NLRP3, and TNF-α decreased in the I/R groups and approached the control group levels with a high dose of avanafil.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

The effect of Sildenafil, a phosphodiesterase-5 inhibitor, on tendon healing: an experimental study in rat model of achilles tendon injury.

INTRODUCTION: Sildenafil Citrate has various effects on the body, including widening blood vessels, inhibiting platelet aggregation, promoting the growth of blood vessels, stimulating apoptosis and adhesion of fibroblasts, and reducing inflammation. This research aims to explore how Sildenafil Citrate affects surgically treated Achilles tendons, both in terms of tissue structure and mechanical properties. MATERIALS AND METHODS: Forty-eight Wistar-albino rats weighing 350-400 g were randomly divided into groups, 6 in each group, as the study group was given Sildenafil Citrate and the control group given saline, respectively. The Achilles tendon rupture model was created under ketamine and xylazine anesthesia. During the entire experiment, rats were housed in eight separate cages, six of them each. The study group and control group of the first group were sacrificed at the end of 1 week, and Achilles tendon samples were taken. After that, Achilles tendon samples were taken after sacrificing the second group at 14 days, the third group at 21 days, and the fourth group at 28 days, respectively. Neovascularization, inflammation, fibrosis and fibroblastic activities of the harvested Achilles tendons were evaluated histopathologically. Biomechanically, stretching was applied to the Achilles tendons and continued until the tendon ruptured. the maximum force values at the moment of rupture were calculated. RESULTS: The mean maximum strength value of group T21, which was given sildenafil citrate for 21 days, was 31.1 ± 4.36 N, and the mean maximum strength value of group C21, which was the control group, was 20.56 ± 6.92 N. A significant difference was observed between the groups (p: 0.008). Group T28 (45.17 ± 5.54 N) also demonstrated greater strength than group C28 (34.62 ± 3.21 N) in the comparison (p: 0.004). The study also noted significant differences between the groups in neovascularization, in the first week, 1 mild, 3 moderate and 2 prominent neovascularization was observed in group T7, in group T28, moderate neovascularization was observed in 4 specimens and prominent neovascularization was observed in 2 specimens (p: 0.001). Furthermore, the groups showed significant differences in their levels of fibrosis, inflammation and fibroblastic proliferation (p: 0.017, p: 0.036, (p: 0.035) respectively). CONCLUSIONS: Study has demonstrated that sildenafil citrate can enhance the biomechanical and histopathological aspects of tendon healing, resulting in a stronger tendon.

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Exploring the Multifaceted Potential of Sildenafil in Medicine.

Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil's therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil's broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.

Avanafil: A comprehensive drug profile.

Avanafil is an oral medication used to treat erectile dysfunction (ED). As a phosphodiesterase type 5 (PDE5) inhibitor, it functions by inhibiting the PDE5 enzyme, which ultimately results in increased levels of cyclic guanosine monophosphate (cGMP) and improved blood flow to the penis. Approved by the FDA in 2012, avanafil is recognised for its rapid onset of action, short half-life, and favourable side-effects profile. While it has been explored for other potential therapeutic applications, its current approved use is limited to ED and should be used as prescribed by a medical professional. This chapter provides a comprehensive review of avanafil, encompassing its nomenclature, physicochemical properties, methods of preparation, and identification. Various techniques for analysing avanafil, such as electrochemical analysis, spectrophotometric, spectrofluorimetric, and chromatographic techniques, are discussed. The pharmacology of avanafil, including its pharmacokinetics and pharmacodynamics, is also examined.

The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload.

While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

Inhibition of PDE-4 isoenzyme attenuates frequency and overall contractility of agonist-evoked ureteral phasic contractions.

The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 µM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 µM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 µM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 µM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.

Sildenafil delays bone remodeling of fractured femora in aged mice by reducing the number and activity of osteoclasts within the callus tissue.

The elderly exhibit a reduced healing capacity after fracture, which is often associated with delayed or failed bone healing. This is due to a plethora of factors, such as an impaired bone vascular system and delayed angiogenesis. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil exerts pro-angiogenic and pro-osteogenic effects. Hence, we herein investigated in aged mice whether sildenafil can improve fracture healing. For this purpose, 40 aged CD-1 mice (16-18 months) were daily treated with 5 mg/kg body weight sildenafil (n = 20) or vehicle (control, n = 20) by oral gavage. The callus tissue of their femora was analyzed at 2 and 5 weeks after fracture by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry as well as Western blotting. These analyses revealed a significantly increased bone volume and higher ratio of callus to femoral bone diameter in sildenafil-treated mice at 5 weeks after fracture when compared to controls. This was associated with a reduced number and activity of osteoclasts at 2 weeks after fracture, most likely caused by an increased expression of osteoprotegerin (OPG). Taken together, these findings indicate that sildenafil does not improve fracture healing in the elderly but delays the process of bone remodeling most likely by reducing the number and activity of osteoclasts within the callus tissue.

Phosphodiesterase type 5 inhibitors do not prevent curvature progression but shorten pain duration in the active phase of Peyronie's Disease: A retrospective cohort study.

Treatment with Phosphodiesterase Type 5 inhibitors (PDE5is) has shown promise in managing Peyronie's disease (PD) during its active phase. In a retrospective cohort study of 133 PD patients, we compared daily PDE5i treatment (sildenafil 25 mg or tadalafil 5 mg) in Group 1 (n = 101) to no treatment in Group 2 (n = 32). The mean age ± SD was 58.5 ± 10, (range: 29-77) years in Group 1 and 59 ± 13.7 years (range: 23-80) in Group 2 (p = 0.5). Mean symptom onset-to-visit time was 10.6 ± 7.2 months (range: 1-37) in Group 1 and 11 ± 6.3 months (range 3-27) in Group 2 (p = 0.5). Mean penile curvature change was +0.87° (95% CI: -1.8, 3.5) in Group 1 and +5.72° (95% CI: 1.4, 10) in Group 2 (p = 0.07) between first and last observations. Group 1 experienced shorter mean pain duration (9.1 ± 4.7 months, range: 2.5-24) than Group 2 (12.2 ± 6.5 months, range: 5-28) (p = 0.04). When controlling for baseline curvature and symptom onset-to-visit time, there were no differences between groups (-4.7, 95% CI: -10, 0.6) (p = 0.08). In conclusion, continuous PDE5i treatment did not affect PD curvature progression but showed a promising effect on pain.

Variable temperature-nuclear magnetic resonance experiment and high-resolution MS/MSn measurement of hydroxycarbodenafil, and its PDE5 inhibitory activity.

Hydroxycarbodenafil, an analogue of carbodenafil, was detected in a dietary supplement in China in 2020. However, previous reports have not identified some carbon signals from the piperazine ring in nuclear magnetic resonance (NMR) experiments. Because the compound contains an amide bond, the reaction was suggested to be characteristic of compounds with rotational isomers. Variable-temperature NMR is used to determine the rotational barrier between different conformations by changing the measurement temperature. Using this technique, we succeeded in obtaining the first distinct data, including the carbon signals of the piperazine ring in the NMR spectrum of hydroxycarbodenafil. We also confirmed that this technique could be applied to other carbodenafil analogues. Multi-stage mass spectrometry (MSn) measurements with a high-resolution mass spectrometer specific to the substructures were performed to develop a protocol for the structural determination of the carbodenafil analogues. In addition, hydroxycarbodenafil was analysed using X-ray crystallography, and its inhibitory activity against phosphodiesterase type 5 (PDE5) was measured. The IC50 value of the inhibitory activity of hydroxycarbodenafil for PDE5A1, a PDE5 isoform, of 2.9 nM was lower than the 4.5 nM for sildenafil, a positive control.