The emerging role for type 5 phosphodiesterase inhibition in heart failure.
Patients with heart failure (HF) due to left ventricular (LV) systolic dysfunction have abnormal endothelium-dependent, nitric oxide-cyclic guanosine monophosphate-mediated vasodilation in the pulmonary and skeletal muscle vasculature. Therefore, inhibition of type 5 phosphodiesterase (PDE5), the principle enzyme responsible for cyclic guanosine monophosphate catabolism in the lungs and skeletal muscle, has been targeted in an effort to counteract vasoconstriction that contributes to increased right and LV afterload in HF. The efficacy of PDE5 inhibition in the treatment of pulmonary arterial hypertension has led to the investigation of its potential utility in the treatment of HF patients with secondary pulmonary hypertension. Moreover, recent preclinical studies suggest direct myocardial effects of PDE5 inhibition that may counteract beta-adrenergic, hypertrophic, and pro-apoptotic signaling, three critical pathways in the development of LV dysfunction. This review outlines both the underlying rationale and the results of initial studies of the therapeutic effects of PDE5 inhibition in HF.
Lewis
Gregory D
GD
Cardiology Division, Bigelow 800, MassachusettsGeneral Hospital, 55 Fruit St., Boston, MA 02114, USA.
Semigran
Marc J
MJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D017079:Exercise Tolerance / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human