title: Clinically relevant concentrations of olprinone reverse attenuating effect of propofol on isoproterenol-induced cyclic adenosine monophosphate accumulation in cardiomyocytes.
abstract: Propofol has been shown to attenuate beta-adrenoreceptor-mediated signal transduction in cardiomyocytes. Cyclic adenosine monophosphate (cAMP) is an essential second messenger of beta-signal transduction, while olprinone, a phosphodiesterase-III inhibitor, improves poor cardiac performance by increasing cAMP levels. In the present study, we investigated the effects of olprinone toward the reducing effect of propofol on beta-adrenoreceptor-mediated increases in cAMP production. First, suspensions of rat ventricular myocytes were incubated with isoproterenol or olprinone and the effects on cAMP concentrations were assessed. Next, propofol was added prior to the addition of isoproterenol or olprinone. Finally, following preincubation with propofol, isoproterenol with or without olprinone was added. Both isoproterenol and olprinone increased cAMP production in a dose-dependent manner. However, clinically relevant concentrations of olprinone (up to 10(-7) M) did not cause a significant increase. Propofol (10(-7)-10(-4) M) attenuated isoproterenol-stimulated increases in cAMP production (decrease of 2 +/- 4% approximately 43 +/- 1%, as compared to the isoproterenol-stimulated state). However, the agent did not alter olprinone (10(-7) M)-stimulated cAMP production. Olprinone (10(-8)-10(-6) M) reversed the attenuating effect of propofol (10(-5) M) toward isoproterenol (10(-7) M)-stimulated cAMP production dose-dependently (increase of 10 +/- 5% approximately 79 +/- 4% as compared to the propofol-attenuated state). Our results suggest that an improvement in cardiac function is provided by olprinone when the beta-adrenoreceptor-mediated signaling pathway is inhibited by propofol.
authors.affiliation: Department of Anesthesiology and Critical Care, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. hiromi_kurokawa@hotmail.com
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kurokawa
authors.forename: Aki
authors.initials: A
authors.lastname: Matsunaga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamada
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Osafumi
authors.initials: O
authors.lastname: Yuge
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015742:Propofol / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D018686:Anesthetics, Intravenous; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011943:Receptors, Adrenergic, beta; C059498:olprinone; D000242:Cyclic AMP; D007545:Isoproterenol; D015742:Propofol