sildenafil-citrate and Albuminuria

Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance.. The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function.. This was a randomized, double-blind, placebo-controlled study.. This trial was conducted at Vanderbilt Clinical Research Center.. Participants included overweight individuals with prediabetes.. Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment.. The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion.. Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation.. Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.

Topics: Adult; Albuminuria; Double-Blind Method; Endothelium, Vascular; Female; Fibrinolysis; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Hemodynamics; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Overweight; Phosphodiesterase 5 Inhibitors; Plasminogen Activator Inhibitor 1; Prediabetic State; Sildenafil Citrate

Sildenafil citrate has shown to display beneficial cardiovascular effects, suggesting that it may have other systemic benefits involving the endothelium. There is little data regarding the long-term use of this drug and the effects of this on different organs.. The primary aim of this study was to determine whether sildenafil citrate diminishes concentrations of microalbuminuria and percentage of A1c in patients with type 2 diabetes.. A double-blind, randomized, controlled trial in 40 male patients, age 35-50, with type 2 diabetes. Subjects received sildenafil citrate 50 mg daily (n=20) or placebo (n=20) for 30 days. Levels of hs-CRP, microalbuminuria, homocysteine, A1c and erectile function were measured at baseline and to the end of the study.. Men that received sildenafil citrate displayed a significant decrease in the microalbuminuria concentrations (p<0.01) versus baseline, (p=0.02) versus placebo and A1c (p<0.01) versus baseline, (p=0.01) versus placebo. In addition, we observed a significant increase in the total IIEF score after 30 days of treatment (p<0.01) versus baseline, (p<0.01) versus placebo.. The administration of 50mg of sildenafil citrate for 30 consecutive days diminishes microalbuminuria and the percentage of A1c in patients with type 2 diabetes.

Topics: Adult; Albuminuria; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Homocysteine; Humans; Male; Middle Aged; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Cyclosporine A (CsA) is the most widely used immunosuppressant in organ transplant surgery and in treatment of autoimmune disease. Nevertheless, animal and clinical studies have demonstrated that nephrotoxicity is the major adverse effect limiting the prolonged CsA therapeutic use. The present study aimed to investigate possible protective effect of sildenafil, a phoshodiestrase-5 inhibitor, on CsA-induced nephrotoxicity and various mechanism(s) underlies this effect. Male Wistar rats were administered CsA (20 mg/kg/day, s.c.) for 21 days alone or in combination with sildenafil (5 mg/kg/day, p.o.). Sildenafil exhibited nephroprotective effects as evidenced by significant decrease in serum creatinine and urea levels, spot urine albumin-creatinine ratio, as well as renal level of malondialdehyde, with a concurrent increase in renal levels of reduced glutathione and nitric oxide along with catalase activity compared to CsA-treated rats. [corrected]. Additionally, immunohistochemical analysis demonstrated that sildenafil treatment markedly reduced inducible nitric oxide synthase, tumor necrosis factor-alpha, and caspase-3 expressions, while expression of endothelial nitric oxide synthase was prominently enhanced. The protective effects of sildenafil were confirmed by renal histopathological examination. Pretreatment with l-nitro-arginine methyl ester (10 mg/kg/day, i.p.), a non-selective nitric oxide synthase inhibitor, reversed the protection afforded by sildenafil. Taken together, the current study highlighted the renoprotective effects of sildenafil against CsA-induced nephrotoxicity in rats, which might be mediated, in part, through nitric oxide pathway as well as antioxidant, anti-inflammatory, and anti-apoptotic activities.

Topics: Albuminuria; Animals; Catalase; Creatinine; Cyclosporine; Glutathione; Immunosuppressive Agents; Kidney Diseases; Male; Malondialdehyde; Nitrates; Nitric Oxide; Nitrites; Phosphodiesterase 5 Inhibitors; Piperazines; Protective Agents; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Urea

It is well established that the pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide (NO) generation. Many of the biological actions of NO are mediated by cGMP, which is rapidly degraded by phosphodiesterases. In this study, we evaluated the renoprotective effects of sildenafil (SIL), an inhibitor of phosphodiesterase-5, in type 2 diabetic rats.. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetes model, and Long-Evans Tokushima Otsuka rats, a non-diabetic control, were treated with either SIL (2.5 mg·kg(-1) in drinking water) or undosed water for 28 weeks, starting at 30 weeks of age.. Sildenafil treatment significantly decreased albuminuria, attenuated glomerular hyperfiltration and resulted in a decrease in glomerular hypertrophy, in addition to a reduced glomerulosclerosis score and a dramatic decrease in the number of glomerular and tubulointerstitial proliferating cell nuclear antigen-positive cells in OLETF rats. This was accompanied by a significant reduction in renal cortical mRNA levels of collagen types I and III. The increased mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 in the OLETF rats were significantly or partially attenuated by SIL treatment.. This study suggests that SIL attenuated diabetic nephropathy due to its potent antiproliferative effects and its regulatory effects on extracellular matrix. This latter effect is thought to be a result of its ability to affect the balance between MMPs and their inhibitors.

Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Cell Proliferation; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney; Kidney Function Tests; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Inbred OLETF; Sildenafil Citrate; Sulfones; Transforming Growth Factor beta1