Cardiovascular implications in the use of PDE5 inhibitor therapy.
Cardiovascular smooth muscle cells (SMCs) exist as resting or activated cells. Resting SMCs produce contractile proteins and are nearly transcriptionally inactive; activated SMCs are transcriptionally active and are involved in pathological processes such as atherosclerosis. Soluble guanylate cyclase, protein kinase G, and protein kinase A are present in SMCs, but their levels can be decreased in activated cells. Phosphodiesterase 3 (PDE3) activity is abundant in cardiovascular tissues; both PDE3A and PDE3B are involved in cyclic adenosine monophosphate (cAMP) hydrolysis in these tissues. Cyclic-AMP-hydrolyzing PDE activities are altered during the phenotypic transition of SMCs from the resting to the activated phenotype. Similar changes have been observed in cyclic guanosine monophosphate cGMP-hydrolyzing PDEs, although the impact of these alterations on PDE5 inhibitor-mediated effects requires further study. This report presents the changes in PDE expression that accompany phenotypic modulation of SMCs and discusses the potential impact of these events on PDE5-mediated cell functions.
Maurice
D H
DH
Department of Pharmacology & Toxicology, Queen's University at Kingston, Kingston, ON, Canada. mauriced@post.queensu.ca
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002319:Cardiovascular System / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004730:Endothelium, Vascular / Q000201:enzymology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006162:Guanylate Cyclase; D006152:Cyclic GMP