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      PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.

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          Abstract

          The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients.

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          Author and article information

          Journal
          Pharmacol. Ther.
          Pharmacology & therapeutics
          1879-016X
          0163-7258
          Mar 2015
          : 147
          Affiliations
          [1 ] Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, United States.
          [2 ] Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: rakesh@vcu.edu.
          Article
          S0163-7258(14)00189-2 NIHMS639679
          10.1016/j.pharmthera.2014.10.003
          4494657
          25444755
          973d71ad-d3fd-4a5e-8e08-b7dabcb33e9e
          Copyright © 2014 Elsevier Inc. All rights reserved.
          History

          Cardioprotections,Chemotherapy,Diabetes,Heart failure,Phosphodiesterase 5,cGMP

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