Phosphodiesterase type 5: expanding roles in cardiovascular regulation.
Phosphodiesterase type 5A (PDE5A) selectively hydrolyzes cyclic GMP. Inhibitors of PDE5A such as sildenafil are widely used to treat erectile dysfunction, but growing evidence supports important roles for the enzyme in both the vasculature and heart. In disorders such as cardiac failure, PDE5A upregulation may contribute to a decline in cGMP and protein kinase G signaling, exacerbating dysfunction. PDE5A plays an important role in the pulmonary vasculature where its inhibition benefits patients with pulmonary hypertension. In the heart, PDE5A signaling appears compartmentalized, and its inhibition is cardioprotective against ischemia-reperfusion and antracycline toxicity, blunts acute adrenergic contractile stimulation, and can suppress chronic hypertrophy and dysfunction attributable to pressure-overload. In this review, we discuss the molecular biology, pharmacology, and physiology of PDE5A, mechanisms of vascular and cardiac regulation, and recent evidence supporting the utility of selective PDE5A inhibition for the treatment of cardiovascular disorders.
Kass
David A
DA
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. dkass@jhmi.edu
Champion
Hunter C
HC
Beavo
Joseph A
JA
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology; D002319:Cardiovascular System / Q000201:enzymology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D010726:Phosphodiesterase Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5