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Inhibition of cGMP catabolism by selective PDE5-Is increases NO levels by increasing the ratio of nitrite to nitrate and by stimulating transcription of mRNA for iNOS, as well as eNOS [17]. In addition, nitric oxide increases in tissues and cells the level of heme oxygenase HO-1 which oxidatively degrades heme into equimolar amounts of CO, biliverdin, and iron. Carbon monoxide activates sGC and elevates cGMP in target tissues, which dilates blood vessels.

Through that stimulation, sildenafil may serve a critical growth of cellular cGMP levels [18]. [17] demonstrated that sildenafil stimulates the expression of HO-1 and iNOS in vascular smooth muscle cells (SMCs) via the reactive oxygen species-nuclear erythroid 2-related factor 2 (ROS-Nrf2) and sGC-cGMP pathways, respectively [17]. Transcription factor Nrf2 is responsible for the induction of phase II enzymes of xenobiotics metabolism.

It activates transcription of genes encoding cytoprotective proteins which deactivates electrophiles metabolites and reactive oxygen species and stabilizes the redox potential of the cell.

Nrf2 controls antioxidant defense genes including HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), gluthatione reductase (GR), and gluthatione peroxidase (GPx) [18, 19]. [20] indicate direct effect of sildenafil on cells.

Sildenafil treatment of astrocytes prevents and also restores effect of LPS on actin filaments.

Changes in actin stress fibres is a result of overactivation of Ca 2+ signaling by LPS.

proposed that sildenafil directly influences cell integrity through ankyrin B, a protein which is associated with the cytoskeleton, and interacts with Na + /K + -ATP-ase and IP 3 R connecting the pump to the Ca 2+ responses from internal cell stores and to the integrity of the cytoskeleton. These data show that cGMP is involved in Na + /K + -ATP-ase activity. Sildenafil acting through Na + /K + -ATP-ase could change Ca 2+ waves and stop the inflammatory process.

The action of sildenafil is amplified through these mechanisms. The Effect of Sildenafil on the Immune System of Healthy Experimental Animals.

There is some evidence that immunomodulatory properties of sildenafil are gender-specific.

In healthy mice, a tendency to decrease the percentage of CD4 + cells and to increase the percentage of CD8 + T cells was demonstrated in males but not females treated with sildenafil [21].

[21] observed that the levels of T effector memory cells and T central memory cells were decreased in males and increased in females.

Naive T cell levels were increased in males, while CD8 + (T central memory) cells were decreased. Interestingly, there was no effect on lymphocyte regulatory T lady viagra tablet buy online cells (Treg) or natural killer T-cells (NKT) in the entire gender-mixed population.

The percentage of the activated NK cells and T conventional cells was increased in the female population and decreased in males. Sildenafil treatment did not affect the percentage of dendritic cells in the whole mouse population. SC in healthy mice led to a decrease in percentage of these cells in the spleen of female mice.

Moreover, sildenafil was found to diminish serum levels of IL-6 in mice and demonstrated a tendency to increase IL-2.

No influence of sildenafil on serum levels of IL-10, IL-1 ? or vascular endothelial grow factor (VEGF) was observed.

Sildenafil revealed a considerable immunosuppressive effect in male as opposed to female mice [21].

The differences in immunological effects of the drug between females and males could be explained by endocrine and genetic differences between the sexes [22]. It should be noted that sildenafil in this study was used in large doses—20 mg/kg for 21 days.

Ex vivo studies of the effects of sildenafil on isolated splenocytes from healthy mice confirmed a lack of influence on the cytotoxicity of mononuclear cells (CD8 + , NKT, and NK cells). SC did not affect either maturation or activation of dendritic cells (DC). But with respect to naive/memory phenotype of T cells sildenafil reduced the amount of CD8 + cells in whole population. Sildenafil at the concentration of 7.5 ? M after 24 h of culture increased the percentage of CD4 + T cells and reduced the percentage of B cells [21]. Szczypka and Obminska-Mrukowicz [23] investigated the effects of sildenafil on thymocytes, splenocytes, and T cells isolated from mice lymph nodes. Oral administration of sildenafil at a dose 1 mg/kg temporarily decreased the percentage of CD4 + CD8 + thymocytes and increased CD8 + cells.

This effect was only observed after the fifth dose of the drug administrated at 24 h intervals.

Among lymphocytes isolated generic viagra teva from the mesenteric lymph nodes, the percentage of CD19 + cells decreased and a rise in the percentage of CD3 + cells was noted 72 h after the last dose of the drug.

In another study researchers used the same protocol of buy generic viagra soft tabs administration of SC to investigate cytokine concentration in animals serum.

Sildenafil decreased IL-2 level after 72 h from a single administration of 1 mg/kg and after 12 h enhanced temporarily the level of IL-5 (from 7 to 13 pg/mL) [24].

Szczypka and Obmiska-Mrukowicz [25] showed that sildenafil increased the production of IL-1 ? and nitric oxide (NO) by peritoneal macrophages ex vivo, increased the percentage of phagocytosing granulocytes, and decreased the percentage of phagocytosing monocytes.

The Effect of Sildenafil on the Experimental Animals Immune System in Pathological Conditions.

PDE5 is present in glial cells and neurons [26, 27].

[29] reported that immunomodulatory therapies can be particularly beneficial in the treatment of multiple sclerosis (MS), a disease in which the immune system reacts against the central nervous system (CNS) antigens, initiating a detrimental inflammatory cascade which leads to demyelination and axonal degeneration.

[30], in their research on experimental autoimmune encephalomyelitis (EAE) as a model of MS, found that administration of sildenafil to mice (10 mg/kg, equivalent to a dose of 57 mg/day for a 70-kg human) for 7 days, at the onset of clinical symptoms, resulted in reduced cellular infiltration in spinal cord and white matter. Sildenafil treatment increased the number of cells expressing the forkhead box p3 (Foxp3) transcription factor, as well as the expression of mRNA of granzyme B (GrB) cluster proteins. CD4 + and CD8 + Treg cells are known to act by granzymes in the inhibition of T effectors cells and antigen presenting cells (APC).

It was shown that GrB protein was upregulated in Treg cells [30].

Moreover, production of IL-2, IFN- ? , and IL-4 in cultures of splenocytes isolated from sildenafil-treated mice was reduced. A tendency to reduce the level of TNF- ? and IL-17 was also observed.

Sildenafil did not change the level of inhibitory cytokine IL-10.

In vitro proliferation of splenocytes from control group mice after stimulation with phytohemagglutinin (PHA) and exposure to sildenafil from 0.1 to 10 ? M/mL was decreased in the SC concentration-dependent manner [30]. Examination of sildenafil-treated EAE mice brains showed that infiltration of inflammatory cells to the brain was reduced due to a lower expression of the intracellular adhesion molecule-1 (ICAM-1).

It was found that sildenafil also decreased the level of autoantibodies against myelin oligodendrocyte glycoprotein viagra tablet online buy in the serum [31].

[32] confirmed a strong anti-inflammatory effect of sildenafil as a result of influence on TNF- ? , IFN- ? , IL-2, and IL-1 ? production in cerebella in sildenafil-treated MS mice.

continued their research [33] in cuprizone- (CPZ-) induced demyelination in mice. Mice treated with sildenafil and CPZ for 15 days had decreased levels of IL-1 ? and TNF- ? in the serum compared to the CPZ group, but sildenafil did not affect concentration of IL-2.

Expression of NO was significantly increased in animals treated with sildenafil, in comparison to the control group. Expression of IL-10 was higher in cerebella from sildenafil-treated mice than in CPZ group.

[34] on placental and trophoblast cells from LPS-induced abortion mice provided insights into protective properties of sildenafil during pregnancy. Orally administered sildenafil blocks transcription of nuclear factor- ? B (NF- ? B) in nuclei of trophoblast cells and decreased the level of proinflammatory cytokines TNF- ? and IL-1 ? in placenta fragments.

P-Selectin (P-Sel) expression was analyzed in the spongiotrophoblast area, where giant trophoblastic cells are predominant.

The LPS-treated group had decreased expression of P-Sel. Sildenafil either alone or in combination with heparin was beneficial for maintaining higher levels of P-Sel, similar to what was found in the control group [35]. Adhesion molecules such as P-selectin play a role in embryo implantation and placentation and can also be a marker of healthy placentas [36, 37].

[39] found that in tumor-bearing mice the inhibition of PDE5 with sildenafil prolongs survival of the animals through the augmentation of antitumor immunity.

This effect was achieved due to the inhibition of myeloid-derived suppressor cells (Gr-1 + CD11b) and downregulation of IL-4R ? .

Consequently, it resulted in the restoration of the CD8 + T cell response. NO-cGMP pathway has neuroprotective and antiapoptotic effects by increasing the level cGMP. Intracellular accumulation of cGMP in different models of inflammation reduces production of proinflammatory cytokines and reduces oxidative stress [25]. [40] aimed to investigate the possible protective effects of sildenafil citrate on tissue integrity, oxidant–antioxidant status, and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Treatment of animals with sildenafil (10 mg/kg subcutaneously for 14 days) was beneficial with regard to prevention of lipid peroxidation, cytokine (IL-1 ? and TNF- ? ) production, neutrophil accumulation, and myeloperoxidase (MPO) activation. [41] showed that sildenafil exerts anti-inflammatory effects in vitro in LPS-activated microglial cells by blocking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF- ? B) and Mitogen Activated Protein Kinase (MAPK) activation. Sildenafil markedly inhibited iROS production induced by LPS, which may be partly due to MAPKs potent downregulation of the NADPH-derived iROS production [40]. [42] found that sildenafil treatment in a murine model of EAE resulted in changes in the expression of several genes implicated in responses to stress and inflammation, as well as genes involved in cytoskeleton reorganization and wound healing. Sildenafil caused 2.5-fold increase of mRNA expression of inflammation-related genes chitinase 3-like 3 (YM-1) protein secreted by peritoneal macrophages.

On the other hand, microglia/macrophages ionized calcium-binding adapter molecule-microglia activation marker (Iba-1) was decreased.

These results suggest that sildenafil promotes a switch from the M1 proinflammatory (M1) to the anti-inflammatory (M2) phenotype macrophages [42].

Macrophages generated from monocytes can differentiate into classically activated M1 or alternatively activated M2. M2 macrophages promote wound healing and secrete TGF- ? , an immunoregulatory and anti-inflammatory cytokine [43, 44].

These results indicate that sildenafil induces a shift from the classical to the alternative microglia/macrophage phenotype which has been associated with neuroprotective functions that promote repair processes and wound healing [44]. Further research on neurodegenerative diseases models by Raposo et al.

[45] demonstrated that sildenafil reduces the expression of cytokines as well as cyclooxygenase-2 (COX-2) and astrocyte activation marker (GFAP) in a demyelinating model induced in wild-type (WT) mice. Sildenafil reduced expression of Iba-1 and increased concentration of IK ?? - NF ? B inhibitory protein in activated M1 macrophages.

The administration of sildenafil decreased expression of NF ? B, GFAP, inactivated AMP-activated protein kinase (AMPK), and iNOS. AMPK is an intracellular energy sensor that plays central role in glucose and lipid metabolism.

It also downregulates inflammation in vitro and in various animal models. NO may act as an endogenous activator of AMPK and in an opposite way inactivates NF ? B by phosphorylation of inhibitor k binding ? (IK ?? ). The study proved that sildenafil exerts its anti-inflammatory effect probably through AMPK-eNOS/NO-NF ? B signaling. Sildenafil can also act directly through cGMP and indirectly by PKA on NF ? B inhibition [45].

Administration of sildenafil reduced the expression of IL-1 ? and TNF- ? and increased the level of anti-inflammatory cytokine IL-10 [41, 45].

There is ample evidence to indicate the role of CCR-2 (monocyte chemoattractant protein 1-MCP-1-receptor-CCl-2) in tissue repair after injury and increased neurogenesis due to its chemotactic property in neural precursor cells [46].

[47] suggested that increase of CCR-2/MCP-1 is associated with the stimulation cGMP-PKG signaling induced by sildenafil, and it can stimulate protective M2 phagocytic phenotype of microglia.

This study also demonstrated that expression of extracellular metalloproteinase-9 (MMP-9) is increased after sildenafil treatment.

Most MMPs are secreted as inactive proteins generic viagra teva generic viagra teva which are activated when cleaved by extracellular proteinases. However, it has been proposed that MMPs have a role in modulating different physiological processes, such as reproduction, angiogenesis, bone development, apoptosis, and cell migration. reported that sildenafil facilitated vascular remodeling by enhancement of MMP-9 expression [47].

Lung ischemia/reperfusion (I/R) injury plays an important role in outcome of organ transplantation.

[48] in studies on rats suggested that watering with saline and sildenafil (10 mg/kg) 3 h before the operation improved lung I/R injury by decreasing the production of IL-6 and TNF- ? .

It has been shown that pretreatment with sildenafil normalizes TNF- ? and IL-6 levels in lung tissue, which suggests that pretreatment with sildenafil alleviated inflammation in early reperfusion injury. Similar findings were reported recently by Zahran et al. [49], after investigation of rats renal ischemia/reperfusion injury.

Watering rats orally with SC 1 mg/kg 60 min before anesthesia resulted in activation of antioxidant genes (Nrf2, HO-1 and NQO-1-quinone oxidoreductase) and antiapoptotic gene (Bcl-2) and attenuation of proinflammatory cytokines (TNF- ? , IL-1 ? ) as well as ICAM-1. Expression of genes was evaluated in ischemic kidney tissue after nephrectomy. Effects of sildenafil were maximal after 2 days from SC administration. The Effects of Sildenafil on the Lymphocytes Subpopulations of Healthy Human Blood Donors.

The only data of the effects of sildenafil on healthy human lymphocytes in vitro comes from Pifarre et al.

[30] studies on human T regulatory cells.Cocultures of T effector cells and T reg cells (0.25 : 1 and 0.5 : 1 ratio) isolated from healthy donor peripheral blood showed that sildenafil at the 10 ? M concentration influenced the ability of Tregs to downregulate T effector cell proliferation. Moreover, expression of Treg transcription factor Foxp3 was increased, suggesting that upregulation of Tregs is involved in T effector cell deactivation.

The Effects of Sildenafil on the Immune System in Patients Treated with Sildenafil.

The influence of sildenafil on the TNF- ? level, Treg, and NK generic viagra with dapoxetine activity in patients with recurrent abortion was reported.

[50] found that sildenafil significantly reduced peripheral blood NK activity in 38 women with natural and after in vitro fertilization (IF) recurrent abortion.