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.