Phosphodiesterase 5A as a target in cardiac disease

Cardiac hypertrophy and doxorubicin cardiotoxicity are causes of heart failure. Recently, studies have been undertaken to ascertain whether or not raising cGMP levels by targeting phosphodiesterase 5A (PDE5A) for inhibition with sildenafil may be useful in these conditions. In two animal models of cardiac hypertrophy (pressure overload in mice, isoprenaline-induced in rats), sildenafil pretreatment has been shown to prevent the development of hypertrophy. More importantly, sildenafil was shown to reverse existing cardiac hypertrophy in the pressure overload model. In mouse electrocardiography, increases in ST-interval duration correlate with doxorubicin-induced cardiotoxicity, and this increase was not observed when the mice were treated with both doxorubicin and sildenafil. Doxorubicin treatment decreased heart rate and left ventricular developed pressure, and these decreases were inhibited by pretreatment with sildenafil. As experiments, in animal models of cardiac hypertrophy and doxorubicin-induced cardiomyopathy, with the PDE5A inhibitor sildenafil have shown beneficial effects, this clearly establishes PDE5A as a target in cardiac disease.