Controllers of cyclic nucleotide signaling
Phosphodiesterases form a superfamily of enzymes that hydrolyze cyclic nucleotides cAMP or cGMP back to AMP or GMP. Of these, both PDE5 and PDE9 are highly selective for cGMP. We were among the first to reveal that PDE5 inhibition (which is achieved by sildenafil or ViagraÒ) protects and reverses pressure-overload-induced heart disease. The study forged over a decade of research, and there are ongoing efforts in humans with reduced function heart failure. In 2015, we first reported that PDE9 inhibition also protects the heart from pressure-overload disease, and showed it targets cGMP synthesized by natriuretic peptides (versus NO). Clinical trials of PDE9 inhibitors have already been started in heart failure patients. We also first reported the use of PDE1 inhibitors in heart failure, showing that this leads to a cAMP-related increase in contractility and vasodilation. This works by mechanisms distinctly different from adrenergic stimulation – but rather is coupled to adenosine signaling.