sildenafil-citrate and Hypercholesterolemia

Hypercholesterolemia is associated with impaired neovascularization in response to ischemia. Potential mechanisms include defective NO bioactivity and a reduction in the number/function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that sildenafil, a phosphodiesterase 5 inhibitor that increases NO-driven cGMP levels, could stimulate EPC function and improve ischemia-induced neovascularization in hypercholesterolemic conditions. Apolipoprotein E-deficient (ApoE(-/-)) mice were treated (or not treated) with sildenafil (40 mg/kg per day in water), and hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to an improved blood flow recovery, an increased capillary density, and a reduction of oxidative stress levels in ischemic muscles at day 7 after surgery. Sildenafil therapy is associated with an increased activation of angiogenic transduction pathways, including Akt, p44/42 mitogen-activated protein kinase, and p38. In vitro, sildenafil increases cellular migration and tubule formation of mature endothelial cells (human umbilical vascular endothelial cells) in a cGMP-dependent manner. In vivo, ApoE(-/-) mice treated with sildenafil exhibit a significant increase in the number of bone marrow-derived EPCs. Moreover, the angiogenic activities of EPCs (migration and adhesion) are significantly improved in ApoE(-/-) mice treated with sildenafil. In summary, this study demonstrates that sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic ApoE(-/-) mice. The mechanisms involve beneficial effects on angiogenic transduction pathways together with an increase in the number and the functional activity of EPCs. Sildenafil could constitute a novel therapeutic strategy to reduce tissue ischemia in atherosclerotic diseases.

Topics: Analysis of Variance; Animals; Apolipoproteins E; Blotting, Western; C-Reactive Protein; Cell Movement; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Hindlimb; Hypercholesterolemia; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Piperazines; Probability; Purines; Random Allocation; Sildenafil Citrate; Stem Cells; Sulfones

This study evaluated the effect of correction of serum cholesterol levels on erectile function and sildenafil treatment in patients with erectile dysfunction who have only hypercholesterolaemia as a risk factor for erectile dysfunction.. Twenty-five patients with a single risk factor (hypercholesterolaemia, serum cholesterol > 200 mg/dl) for erectile dysfunction were included in the study. The patients were recommended to take sildenafil (minimum two 100 mg tablets/week) 1 h before sexual intercourse for 4 weeks. After 1 month washout period, the patients received a single dose of atorvastatin 10 mg/day for 1 month. Similarly, after a 1 month washout period, atorvastatin 10 mg/day and sildenafil (minimum two 100 mg tablets/week) were administered for 1 month as combination therapy. Erectile function was evaluated before and after all treatment regimens using the International Index of Erectile Function (IIEF).. Following each treatment modality mean IIEF scores were significantly higher than baseline IIEF scores (p < 0.01). The IIEF score after sildenafil treatment was significantly higher than in the atorvastatin treatment group (p < 0.01); and the IIEF score after combined treatment was significantly higher than in the sildenafil and atorvastatin treatment groups.. Correction of serum cholesterol levels with atorvastatin could improve erectile function in patients who have only hypercholesterolaemia as a risk factor for erectile dysfunction. Furthermore, atorvastatin could improve sildenafil's effects on erectile function in hypercholesterolaemic patients with erectile dysfunction.

Topics: Adult; Aged; Anticholesteremic Agents; Atorvastatin; Cholesterol; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Heptanoic Acids; Humans; Hypercholesterolemia; Impotence, Vasculogenic; Male; Middle Aged; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrroles; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler, Duplex

To investigate the effects of hypercholesterolaemia (HC) on rabbit corpus cavernosa in vivo and in vitro, and evaluate the efficacy of vardenafil and sildenafil in normal and HC rabbits, as the phosphodiesterase-5 (PDE-5) inhibitors vardenafil and sildenafil are widely used for treating erectile dysfunction (ED) and most organic causes of ED are associated with vascular risk factors like HC.. Male New Zealand White rabbits were randomly divided into two groups; 11 HC rabbits were fed a 2% cholesterol diet, and 12 age-matched control rabbits received a regular diet. After 12-14 weeks, erectile responses to intravenous sodium nitroprusside (SNP) and PDE-5 inhibitors were evaluated for 2 h in conscious rabbits. Penile length was measured and the area under the curve calculated. Relaxant responses of corpus cavernosal strips to electrical-field stimulation (EFS) were measured before and after exposure to PDE-5 inhibitors and the nitric oxide synthase inhibitor N'-nitro-L-arginine methyl ester.. HC rabbits had a lower erectile response to SNP than controls; in both control and HC rabbits there was a greater erectile response after simultaneous exposure to SNP and vardenafil, or SNP and sildenafil. However, the responses of the HC rabbits were still significantly less than those of the controls. Corpora from control rabbits responded to EFS with greater relaxations at all frequencies, except 1 Hz. Corpora from both HC and control rabbits had greater responses to EFS after exposure to vardenafil and sildenafil; N'-nitro-L-arginine methyl ester diminished the response to EFS.. There was a significantly lower in vivo and in vitro erectile response in HC rabbits than in controls; erectile function measured in conscious rabbits can be used to assess quantitatively the efficacy of different agents, e.g. sildenafil and vardenafil, in pathological animals. In addition, both agents improve in vitro responses of erectile tissue from HC rabbits to EFS.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Area Under Curve; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Hypercholesterolemia; Imidazoles; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Penile Erection; Penis; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rabbits; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.

Topics: Acetophenones; Allopurinol; Animals; Carbachol; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hypercholesterolemia; In Vitro Techniques; Male; Muscle Relaxation; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Onium Compounds; Oxadiazoles; Penis; Phosphodiesterase Inhibitors; Piperazines; Purines; Quinoxalines; Rabbits; Rotenone; Sildenafil Citrate; Sulfones; Superoxides; Uncoupling Agents; Xanthine Oxidase

Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Contraindications; Erectile Dysfunction; Humans; Hypercholesterolemia; Male; Middle Aged; Myocardial Infarction; Nitrates; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Self Administration; Sildenafil Citrate; Sulfones

Topics: Adult; Coronary Disease; Electrocardiography; Emergency Treatment; Humans; Hypercholesterolemia; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Syncope