title: Type IV phosphodiesterase inhibition improves cardiac contractility in endotoxemic rats.
abstract: Type IV phosphodiesterase inhibitors have a potential role in treating human sepsis. We examined the cardiac performance effects of type IV phosphodiesterase inhibition in vivo, in the absence and presence of catecholamines. Rats were randomized to receive either 4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724) at 0 (vehicle), 2 or 10 microg/kg/min. Utilizing a left ventricular catheter to measure cardiac performance, each animal received each of the two catecholamines, epinephrine and norepinephrine, in randomized order. Rats then received intravenous endotoxin and additional infusions of catecholamines. Ro 20-1724 at 2 microg/kg/min protected cardiac contractility during endotoxemia, and at 10 microg/kg/min increased cardiac contractility and protected cardiac function during endotoxemia. Neither dose interfered with the maximal contractile response to catecholamines. Type IV phosphodiesterase inhibition with Ro 20-1724 exerts beneficial effects on cardiac performance during septicemia in an in vivo animal model. Clinical studies of type IV phosphodiesterase inhibitors in critically ill patients are indicated.
authors.affiliation: Department of Critical Care Medicine, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 17033, USA. nthomas@psu.edu
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Thomas
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Carcillo
authors.forename: William A
authors.initials: WA
authors.lastname: Herzer
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000494:pharmacology; D000242:Cyclic AMP / Q000652:urine; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000008:administration & dosage; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002395:Catecholamines; D004731:Endotoxins; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C044101:endotoxin, Escherichia coli; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4