Phosphodiesterase Type 5 Inhibitors Improve Endothelial Function and May Benefit Cardiovascular Conditions

ArticleinThe American journal of medicine 126(3):192-9 · March 2013with18 Reads
DOI: 10.1016/j.amjmed.2012.08.015 · Source: PubMed
Abstract
The effects of phosphodiesterase type 5 inhibitors on vasodilation mediated via nitric oxide-cyclic guanosine monophosphate are well described. Less is known about other mechanisms through which phosphodiesterase type 5 inhibitors benefit endothelial function, including normalization of serum biomarkers, increased levels of endothelial progenitor cells, ischemia-reperfusion protection mechanisms, and other actions specific to patients with diabetes. These various mechanisms are reviewed. Their impact on several cardiovascular diseases, including erectile dysfunction, pulmonary hypertension, heart failure, high-altitude pulmonary edema, Raynaud's phenomenon, coronary artery disease, diabetes, and atherosclerosis, is presented.
    • "Both atorvastatin and sildenafil upregulate intracellular signaling pathways involved in the vascular nitric oxide (NO) sig- naling [44] . Atorvastatin increases endothelial NO synthase expression and activity, thus increasing NO production [42,44], whereas sildenafil inhibits phosphodiesterase-5, increasing cyclic GMP tissue levels [45]. Interestingly, while the combination of both drugs resulted in improved effects in previous studies [20– 22], the same was not true in our 2K1C hypertension model and vascular remodeling, and therefore pathways activated by cGMP may not be critically involved in the effects reported here. "
    [Show abstract] [Hide abstract] ABSTRACT: Imbalanced matrix metalloproteinase (MMP)-2 activity and transforming growth factor expression (TGF-β) are involved in vascular remodeling of hypertension. Atorvastatin and sildenafil exert antioxidant and pleiotropic effects that may result in cardiovascular protection. We hypothesized that atorvastatin and sildenafil alone or in association exert antiproliferative effects by down-regulating MMP-2 and TGF-β, thus reducing the vascular hypertrophy induced by two kidney, one clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral atorvastatin 50 mg/kg, sildenafil 45 mg/kg, or both, daily for 8 weeks. Blood pressure was monitored weekly. Morphologic changes in the aortas were studied. TGF-β levels were determined by immunofluorescence. MMP-2 activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence. The effects of both drugs on proliferative responses of aortic smooth muscle cells to PDGF and on on MMP-2 activity in vitro were determined. Atorvastatin, sildenafil, or both drugs exerted antiproliferative effects in vitro. All treatments attenuated 2K1C-induced hypertension and prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats. Aortas from 2K1C rats showed higher collagen deposition, TGF-β levels and MMP-2 activity and expression when compared with Sham-operated animals. Treatment with atorvastatin and/or sildenafil was associated with attenuation of 2K1C hypertension-induced increases in these pro-fibrotic factors. However, these drugs had no in vitro effects on hr-MMP-2 activity. Atorvastatin and sildenafil was associated with decreased vascular TGF-β levels and MMP-2 activity in renovascular hypertensive rats, thus ameliorating the vascular remodeling. These novel pleiotropic effects of both drugs may translate into protective effects in patients.
    Full-text · Article · Sep 2015
    • "Although the etiology of DM-induced ED is multifactorial and still unknown, endothelial dysfunction is thought to be one of the key factors. Patients with DM and ED often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase (PDE)5 inhibitors [2]. Tadalafil is a PDE5 inhibitor that is safe and efficacious for treating ED across a variety of clinical populations, including patients with many risk factors [3] . "
    [Show abstract] [Hide abstract] ABSTRACT: We studied the relative importance of high-sensitivity C-reactive protein (hs-CRP) concentrations in patients with erectile dysfunction (ED) and diabetes and determined whether the hs-CRP level predicts the response to treatment with 5 mg tadalafil once daily. We enrolled 102 men (aged 40-60 years) with diabetes and ED. All patients completed the International Index of Erectile Function (IIEF) questionnaire and were given 5 mg tadalafil daily. The IIEF and serum hs-CRP levels in patients and healthy controls and in patient responders and nonresponders to 5 mg tadalafil once daily were compared. Median age was 53.2 years (range, 45 to 62 years) in patients and 55.6 years (range, 47 to 64 years) in healthy controls (p=0.158). The median duration of diabetes was 54.3 months (range, 34 to 70 months). The median IIEF and hs-CRP level were 12.1 (range, 5 to 20) and 0.21 mg/dL (range, 0.05 to 0.6 mg/dL) in patients and 28.2 (range, 13 to 31) and 0.09 mg/dL (range, 0.04 to 0.2 mg/dL) in the controls, respectively (pIIEF=0.000, pCRP=0.031). After tadalafil treatment, 71 patients (69.6%) achieved an erection sufficient for sexual intercourse, whereas 31 (30.4%) did not. The median age of the tadalafil nonresponders was 56.2 years (range, 45 to 64 years) and that of the responders was 51.3 years (range, 42 to 62 years; p=0.065). Median hs-CRP levels were 0.31 mg/dL (range, 0.18 to 0.62 mg/dL) in nonresponders and 0.14 mg/dL (range, 0.09 to 0.4 mg/dL) in responders, respectively (p=0.028). Serum hs-CRP was significantly higher in patients with ED and diabetes mellitus than in patients without ED. A significant correlation was observed between serum hs-CRP levels, the degree of ED, and responsiveness to tadalafil.
    Full-text · Article · Dec 2013
  • Article · Jan 2013 · Korean journal of urology
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