Abstract 278: Phosphodiesterase-5 is Highly Expressed in the Hypertrophied Human Right Ventricle and Acute Inhibition Causes Increased Contractility via cGMP-Inhibition of Phosphodiesterase-3
Background: Sildenafil was recently approved for the treatment of Pulmonary Arterial Hypertension (PAH). The beneficial effects of phopshodiesterase type 5 (PDE5) inhibitors in PAH are thought to result from relatively selective vasodilatory and anti-proliferative effects on the pulmonary vasculature; and are thought to spare the myocardium, based on early data showing lack of significant PDE5 expression in the normal heart.
Methods and Results: We studied surgical specimens from 9 patients and show for the first time that, while PDE5 is not expressed in the myocardium of the normal human right ventricle (RV), mRNA and protein are markedly up-regulated in hypertrophied RV (RVH) myocardium. PDE5 is also up-regulated in rat RVH. PDE5 inhibition (with either MY-5445 or sildenafil) significantly increases contractility, measured in the perfused heart (modified Langendorff preparation) and isolated cardiomyocytes, in the hypertrophied, but not normal, RV. PDE5 inhibition leads to increase in both cGMP and cAMP in the RVH but not normal RV. Protein kinase-G (PKG) activity is suppressed in RVH, explaining why the PDE5 inhibitor-induced increase in cGMP does not lead to inhibition of contractility. Rather, this leads to inhibition of the cGMP-sensitive PDE3, explaining the increase in cAMP and contractility. This is further supported by our findings that in RVH protein kinase A inhibition completely inhibits PDE5-induced inotropy, while PKG inhibition does not.
Conclusions: The ability of PDE5 inhibitors to increase RV inotropy and decrease RV afterload, without significantly affecting systemic hemodynamics, makes them ideal for the treatment of diseases affecting the RV, including PAH.