Sildenafil In Rats Research Articles

Dapagliflozin, sildenafil and their combination in monocrotaline-induced pulmonary arterial hypertension

BackgroundDapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH).MethodsA monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments.ResultsDapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone.ConclusionsDapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.

Influence of methylxanthines isolated from Bancha green tea on the pharmacokinetics of sildenafil in rats.

Sildenafil is used to treat erectile dysfunction and pulmonary arterial hypertension and is metabolized in the liver mainly by CYP3A4, thus co-administration with drugs or herbal extracts that affect CYP3A4 activity may lead to drug-drug or drug-herb interactions, respectively. The aim of the present study was to evaluate the influence of single and multiple oral doses of methylxanthine fraction, isolated from Bancha green tea leaves on the pharmacokinetics of sildenafil in rats. Rats were given sildenafil alone as well as simultaneously with methylxanthines or ketoconazole. The plasma concentrations of sildenafil were measured with high-performance liquid chromatography method with ultraviolet detection. The pharmacokinetic parameters of sildenafil were calculated by non-compartmental analysis. Concomitant use of sildenafil with a single oral dose of methylxanthines resulted in a decrease in Cmax (p > 0.05), AUC0-t (p < 0.05) and AUC0-inf (p < 0.05), while the administration of sildenafil after methylxanthines pretreatment resulted in an increase in Cmax (p < 0.0001), AUC0-t (p < 0.0001) and AUC0-inf (p < 0.001) compared to the sildenafil group. After co-administration of sildenafil and ketoconazole, a significant increase in Cmax, AUC0-t and AUC0-inf was observedin both of the experiments. Drug-herb interactions were observed when sildenafil was co-administered with Bancha methylxanthines in rats. Further in vivo studies about the potential drug interactions between sildenafil and methylxanthines, especially caffeine, are needed to clarify mechanisms underlying the observed changes in sildenafil pharmacokinetics.

Influence of Energy Drinks on Pharmacokinetic Parameters of Sildenafil in Rats

Both sildenafil and RED BULL®(energy drink) are claimed to boost up energy.RED BULL®, one of the most commonly used energy drinks and its easily and widely available for daily use, the idea of this research work had arisen from observations about the concomitant use of sildenafil with RED BULL® by men seeking for better sexual performance. To study the effect of RED BULL® on the pharmacokinetic profile of sildenafil by using HPLC.The pharmacokinetic parameters (Cmax, Tmax and AUC) were determined in 10 rats following oral administration of 0.57 mg/ml sildenafil with and without RED BULL® in crossover design, to achieve this purpose,simple, rapid and accurate method for validation and determination of sildenafil in rat plasma in the presence of RED BULL® has been developed. This was performed using High-Performance Liquid Chromatography- Ultra Violet (HPLC-UV). The pharmacokinetic data showed that sildenafil plasma level was lower when combined with RED BULL® According to the results obtained, maximum concentration (Cmax) for sildenafil alone was (162.05 ng/ml) after 0.5 hours of administration. The Cmax decreased to (44.68 ng/ml) after 0.5 hoursof administration RED BULL® concomitantly with sildenafil which showed a significant effect on sildenafil plasma level (P&lt;0.001). The area under the curve (AUC) decreased significantly from (370.53 ng/ml*hr) for sildenafil alone to (87.74 ng/ml*hr) when combined with RED BULL®. RED BULL® can alter sildenafil pharmacokinetic if they were taken together.

Prevention of selenite‐induced cataractogenesis by sildenafil in rats

PurposeTo evaluate the effect of sildenafil on selenite‐induced cataract formation in a rat model.MethodsTwenty‐six Wistar rat pups were divided into four groups. Seven pups received only selenite on postpartum day 10 (group 1), 7 pups received selenite and additional high dose sildenafil on postpartum day 10 (group 2), 6 pups received selenite and additional low dose sildenafil on postpartum day 10 (group 3), and 6 pups received only saline (group 4, control). All pups were examined for the presence of cataract under the microscope, starting from the day their eyes opened. Nitrite oxide metabolites, advanced oxidation protein products and total sulfhydryl levels were evaluated in both serum and lenticular samples.ResultsIn group 3, the extent of lens opacification was significantly less than that of selenite‐injected untreated rats (group 1) (p &lt; 0.05). None of the rats in group 4 developed any lens opacity. In lenticular samples, nitrite oxide metabolites level was statistically lower in group 3 compared to group 1 (p &lt; 0.05). In serum, advanced oxidation protein products and total sulfhydryl levels was statistically lower in group 3 compared to group 1 (p &lt; 0.05).ConclusionsLow dose sildenafil appears to inhibit selenite‐induced cataractogenesis in the rat model, and this seems to be caused by the prevention of oxidative damage.

Pharmacokinetic interaction between Kaempferia parviflora extract and sildenafil in rats.

Kaempferia parviflora (KP) is a plant widely used in Southeast Asia. Its major compounds are 3,5,7,3',4'-pentamethoxyflavone (PMF), 5,7,4'-trimethoxylflavone (TMF), and 5,7-dimethoxyflavone (DMF). This study investigated the effect of KP extract on the blood levels and pharmacokinetics of sildenafil co-administration in rats. Rats were randomly assigned to four groups. Groups 1, 2, and 3 were given sildenafil 20mg/kg daily for 9days. On days 4-9 of each treatment period, the treated rats received KP extract (250mg/kg) and vehicle (groups 2 and 3, respectively). Group 4 received KP extract only (250mg/kg daily for 9days). Daily blood concentrations of sildenafil, PMF, TMF, and DMF were determined by HPLC to evaluate the daily blood level interactions. Additional blood samples were collected at various times on the last day of treatment to evaluate the pharmacokinetic interactions. The KP extract decreased blood levels of sildenafil on the first day of co-administration by 95% but the percentage reduction was insignificant on subsequent days. When co-administered with KP extract, the area under the curve (AUC), maximum concentration (C max), and half-life (T 1/2) of sildenafil were decreased by 60-65, 40-52, and 32-54%, respectively, with the elimination rate constant (K e) increased by 37-77%. In addition, PMF, TMF, and DMF concentrations and their AUC, C max, T max, K e, and T 1/2 values were changed after co-administration of KP extract and sildenafil.

Circulation: Heart Failure Editors’ Picks

Summary : Lifelong exercise training maintains a youthful compliance of the left ventricle (LV), whereas a year of exercise training started later in life fails to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products. Alagebrium is a novel drug that breaks advanced glycation end product crosslinks and improves LV stiffness in aged animals. In this study, the authors prescribed alagebrium (200 mg daily) or placebo combined with aerobic exercise training or contact control in healthy, sedentary older individuals for 1 year. The authors evaluated overall cardiac function by the use of several modalities, including invasive pressure–volume measurements, exercise testing, and cardiac MRI before and after the training. To the authors’ knowledge, this is the first study to evaluate the effects of alagebrium and exercise training in healthy aged humans. After intervention, exercise training significantly increased exercise capacity, LV mass, and LV end-diastolic volume. Conversely, alagebrium had little effect on exercise capacity or LV geometry. However, alagebrium showed a modest improvement in LV stiffness compared with placebo. This favorable effect of alagebrium on LV stiffness was most prominent in individuals with combined alagebrium and exercise training. Conclusions : Alagebrium had no effect on hemodynamics, LV geometry, or exercise capacity in healthy, previously sedentary seniors. However, it did show a modestly favorable effect on age-associated LV stiffening.1 Summary : Maximum oxygen consumption (peak VO2) and efficiency of ventilation (VE) during exercise (VE/VCO2 slope) are known to stratify adults in heart failure for 1-year survival. On the basis of adult data, a recent American Heart Association scientific statement suggested that peak VO2<50% predicted for age and sex should be considered substantial impairment in exercise performance in children with heart disease and therefore a class I indication for heart transplant listing. This single-center study examined the association of …

High Performance Liquid Chromatography Method to Detect Tramadol and Sildenafil in the Blood of Rats on Combination Treatment.

Tramadol is one of widest abusedstreet drug inEgypt. Recently, drug abusers were taking tramadol beside sildenafil for sexual purposes.So it was important to develop a newHPLC method for the simaultineous determination of tramadol andSildenafil in the blood of rats exposed to a combination of specific dose of tramadol and sildenafil. Sample preparation involved liquid–liquid extraction with methyl tertiary butyl ether (MTBE) and backextraction with hydrochloric acid.Tramadol,sildenafiland the internalstandardnalbuphine were separated by reversed phaseHPLCusing60%acetonitrileand 40% 20mMsodium phosphate bufferpH 7.5. Detection was by using UV at wavelengths 230 nm. The method was linear fortramadol (0.8–100ug/ml) and Sildenafil (0.3–100 ug/ml) with mean recoveries of 97.2% and 100.8%, respectively. Intra- and inter-day precisionswere 9.34% and 9.12% for tramadol and 11.82%, and10.43% for sildenafilat the respective limits of quantitation (0.8 and 0.3ug/ml). Accuracy fortramadol and Sildenafil ranged from 96.6% to 97.8%and 99.2% to 101.3% respectively. The method was applied to apharmacokinetic study of tramadol and sildenafil in rats.

Herb-Drug Interaction of Epimedium sagittatum (Sieb. et Zucc.) Maxim Extract on the Pharmacokinetics of Sildenafil in Rats

Epimedium sagittatum (Sieb. et Zucc.) Maxim is one of the herbs used to treat erectile dysfunction in Traditional Chinese Medicine. Sildenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction in Western Medicine. This study evaluates the herbal-drug interaction of Epimedium sagittatum extract on the pharmacokinetics of sildenafil in rats by ultra-performance liquid chromatography. The rat plasma was sampled from each anesthetized rat after pretreatment with 3-days Epimedium sagittatum extract (1/2 g/kg/day) and intravenous injection with sildenafil (10/30 mg/kg). The pharmacokinetic data demonstrate that the area under the concentration-time curve (AUC) of sildenafil (10 mg/kg) was significantly decreased in groups that received a high dose of Epimedium sagittatum extract. In conclusion, the study demonstrates that there was significant herb-drug interaction of Epimedium sagittatum extract on the pharmacokinetics of sildenafil at low and high daily doses, suggesting co-administration use of Epimedium sagittatum extract and sildenafil in clinical practice should be prevented due to possible herb-drug interactions.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies

The phosphodiesterase (PDE) 5 inhibitor sildenafil has been shown to display psychotropic actions in humans and animals, and has been used for the treatment of antidepressant-associated erectile dysfunction. However, its effects on the neurobiology of depression are unknown. Nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) inhibition is anti-depressant in animals, and increasing cGMP with sildenafil is anxiogenic in rodents. Substantial cholinergic-nitrergic interaction exists in the brain, while sildenafil shows modulatory actions on cholinergic transmission. Depression is also associated with increased cholinergic drive. Here we report that sildenafil increases muscarinic acetylcholine receptor (mAChR) signaling in human neuroblastoma cells. We also show that fluoxetine (20 mg/kg/day x 7 days), as well as a combination of sildenafil (10 mg/kg/day x 7 days) plus the antimuscarinic atropine (1 mg/kg/day x 7 days) demonstrates significant, comparable antidepressant-like effects in the rat forced swim test (FST) and also reduces cortical beta-adrenergic receptor (beta-AR) density, while sildenafil or atropine alone did not. Importantly, sildenafil did not modify fluoxetine's response. Sildenafil thus demonstrates antidepressant-like effects but only after central muscarinic receptor blockade, providing evidence for cholinergic-nitrergic interactions in the neurobiology of depression.

The Role of Opioid Receptor on the Analgesic Action of Intrathecal Sildenafil in Rats

transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. Methods: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. Results: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. Conclusions: Sildenafil is active against the nociceptive state that's evoke d by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level. (Korean J Pain 2007; 20: 21�� 25)

Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5–50 μg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N- l-nitro-arginine methyl ester ( l-NAME, nitric oxide (NO) synthase inhibitor, 1–50 μg), 1 H-(1,2,4)-oxadiazolo(4,2- a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1–10 μg), KT5823 (protein kinase G (PKG) inhibitor, 5–500 ng), charybdotoxin (large-conductance Ca 2+-activated K + channel blocker, 0.01–1 ng), apamin (small-conductance Ca 2+-activated K + channel blocker, 0.1–3 ng) and glibenclamide (ATP-sensitive K + channel blocker, 12.5–50 μg), but not N- d-nitro-arginine methyl ester ( d-NAME, 50 μg) or saline, significantly diminished sildenafil (50 μg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not l-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO–cyclic GMP–PKG–K + channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca 2+-activated K + channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.

The Effect of Sildenafil on Pulmonary Embolism-Induced Oxidative Stress and Pulmonary Hypertension

Acute pulmonary embolism (APE) is a major cause of pulmonary hypertension and death. We examined the effects of sildenafil on the hemodynamic changes caused by APE in anesthetized dogs. Sham-operated dogs (n = 3) received only saline. APE was induced by stepwise IV injections of 300 mum microspheres in amounts adjusted to increase mean pulmonary artery pressures by 20 mm Hg. Hemodynamic evaluation was performed at baseline, after APE was induced, and then after sildenafil 0.25 mg/kg (n = 8), or sildenafil 1 mg/kg + 0.3 mg . kg(-1) . h(-1) (n = 8) or saline (n = 9) infusions were started. Similar experiments were conducted to examine the effects of sildenafil in rat isolated perfused lung preparation. Plasma thiobarbituric acid reactive species were also determined in both studies to measure oxidative stress. Both doses of sildenafil reduced mean pulmonary artery pressures in dogs by approximately 8 to 16 mm Hg (both P < 0.05) and attenuated the increase in oxidative stress after APE. Mean arterial blood pressure remained unaltered after both doses of sildenafil. Sildenafil produced similar effects after APE in rat isolated perfused lung preparation. These findings indicate that IV sildenafil can selectively attenuate the increases in mean pulmonary artery pressures after APE, possibly through antioxidant mechanisms.

Sildenafil in rats with cirrhosis and portal hypertension: Systemic and splanchnic haemodynamic effects

increased alter PVL in the absence of indomethacin treatment [n contrast, PSS was elevated in both PVL and PVL-indo when compared to sham and sham-indo groups. To delineate the isoinrm of cyclooxygenase involved, Cox-1 -A and Cox-2 4mice were sutNected to sham in=4) or PVL in=7) and after 7 days SPP, abdominal aortic flow and PSS were evaluated Contrary to the pharmacological blockade of Cox, the targeted deletinn ot the Cox1 or Co>2 isoforms in isolation was not able to abrogate the devated hemodynamms observed with experimental PHT.

Hypotensive interaction between Nicorandil and Sildenafil in rat

Hypotensive interaction between Nicorandil and Sildenafil in rat