sildenafil-citrate and vinpocetine

Diclofenac, one of the most commonly used non-steroidal anti-inflammatory drugs, leads to severe adverse effects on the kidneys. The aim of the present study was to investigate the potential pretreatment effect of phosphodiesterase (1, 3 & 5) inhibitors on diclofenac-induced acute renal failure in rats. Rats orally received pentoxifylline (100 mg/kg), vinpocetine (20 mg/kg), cilostazol (50 mg/kg), or sildenafil (5 mg/kg) once per day for 6 consecutive days. Diclofenac (15 mg/kg) was injected on day-4, -5 and -6 in all groups except normal control group. The used phosphodiesterase inhibitors significantly reduced the diclofenac-induced elevation in the serum levels of blood urea nitrogen, creatinine and cystatin C. Moreover, the renal tissue contents of tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB as well as the protein expression of toll-like receptor (TLR) 4 and high mobility group box (HMGB) 1 were markedly reduced by the used phosphodiesterase inhibitors, as compared to the diclofenac control. This was reflected on the marked improvement in histopathological changes induced by diclofenac. Sildenafil showed the best protection regarding TNF-α and NF-κB, while cilostazol showed the best results regarding TLR4, HMGB1 and histopathological examination. This study revealed the good protective effect of these phosphodiesterase inhibitors against diclofenac-induced acute renal failure.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cilostazol; Creatinine; Diclofenac; Kidney; Male; NF-kappa B; Pentoxifylline; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Sildenafil Citrate; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Vinca Alkaloids

The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity.. Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified.. Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE.. The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. FUND: This study was funded by an mRACE Erasmus MC grant.

Topics: Adult; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphodiesterase 5 Inhibitors; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger; Sildenafil Citrate; Vasodilation; Vinca Alkaloids

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Male; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Renal Artery; Renal Circulation; Sildenafil Citrate; Vasodilation; Vasodilator Agents; Vinca Alkaloids

Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3' 5'-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng·min(-1)) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (E(max)168% ± 8% vs 136% ± 4%) and small mesenteric arteries (SMA; E(max)170% ± 6% vs 143% ± 3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E(max)94% ± 12%) but not in controls (154% ± 7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1 ± 0.1 vs 5.9 ± 0.06), but not in controls (6.0 ± 0.03 vs 6.1 ± 0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (E(max)82% ± 12% vs 445 ± 5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1 ± 0.3 vs 5.3 ± 0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.

Topics: Analysis of Variance; Angiotensin II; Animals; Antihypertensive Agents; Arteries; Blood Pressure; Blotting, Western; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Dose-Response Relationship, Drug; Hypertension; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasoconstriction; Vinca Alkaloids

It has been suggested that the capability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil citrate (VIAGRA) to retard the ejaculatory response may include modulation of the contraction of seminal vesicle (SV) smooth muscle. In fact, it has been shown that PDE inhibitors can reverse the tension of isolated human SV tissue and enhance the production of cyclic AMP and cyclic GMP.. The aim of this study was to examine the effects of selective phosphodiesterase (PDE) inhibitors on both the spontaneous and electrically induced phasic contractions of isolated human SV smooth muscle.. To measure the inhibition exerted by PDE inhibitors vinpocetine (PDE1-inhibitor), rolipram (PDE4-inhibitor), sildenafil, and vardenafil (PDE5-inhibitors) on the phasic contractile response of isolated SV tissue.. Using the organ bath technique, the effects of increasing concentrations of the PDE inhibitors (1 nM-10 microM) were investigated on phasic contractions of SV tissue strips either mediated by means of electrical field stimulation (EFS) or the alpha(1)-adrenoceptor agonist norepinephrine.. The contractile activity in response to EFS was dose-dependently reversed by the PDE inhibitors. The rank order of efficacy was: rolipram > sildenafil >or= vardenafil > vinpocetine. Mean maximum inhibition of contraction was determined as -89.6% (rolipram), -61.3% (sildenafil), -62% (vardenafil), and -46% (vinpocetine). No differences were registered with regard to the effects of sildenafil and vardenafil on the inhibition of the contraction amplitudes. The frequency of the spontaneous contractions (amplitudes/5 minutes) was reduced by 50% in the presence of 2 microM rolipram, 5 microM sildenafil or vardenafil, and 8 microM vinpocetine.. Our results demonstrate that PDE inhibitors can inhibit EFS-induced and spontaneous contractile activity of isolated human SV tissue. These findings might be of importance with regard to the pharmacological treatment of premature ejaculation.

Topics: Adrenergic Agents; Aged; Anticonvulsants; Ejaculation; Electric Stimulation; Humans; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Seminal Vesicles; Sildenafil Citrate; Sulfones; Vinca Alkaloids

To further elucidate the significance of the cyclic nucleotide-mediated signal transduction, we examined the in vitro functional responses of isolated seminal vesicle (SV) smooth muscle tissue to selective phosphodiesterase (PDE) inhibitors.. Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE inhibitors vinpocetine (PDE1 inhibitor), rolipram (PDE4 inhibitor), and sildenafil and vardenafil (PDE5 inhibitors) on the tension induced by 10 microM of norepinephrine on SV tissue strips were investigated. To examine the drug effects on the tissue levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the SV strips were exposed to different concentrations of the compounds (0.1, 1, and 10 microM). After freezing, homogenization, and extraction of cyclic nucleotides, cAMP and cGMP were measured using radioimmunoassays. In the experiments, sodium nitroprusside and forskolin were used as reference compounds.. The norepinephrine-induced tension was reversed by the drugs in a dose-dependent manner. The rank order of efficacy was rolipram greater than sildenafil greater than vardenafil greater than or equal to vinpocetine greater than sodium nitroprusside greater than forskolin. The reversion of the norepinephrine-induced tension at maximum drug concentration ranged from 79% (rolipram) to 32% (forskolin). Only rolipram and sildenafil reached a median effective concentration. The effects of the PDE inhibitors were paralleled by a 1.7-fold to 173-fold increase in tissue cGMP or cAMP.. Our results have demonstrated that PDE inhibitors can reverse the adrenergic tension of human SV tissue and increase levels of cyclic nucleotides. This outlines the potential significance of cAMP and cGMP in the control of SV smooth muscle function. These findings might be of importance with regard to the pharmacologic treatment of premature ejaculation.

Topics: Dose-Response Relationship, Drug; Humans; Imidazoles; In Vitro Techniques; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Rolipram; Seminal Vesicles; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride; Vinca Alkaloids