title: Single inhibition of either PDE3 or PDE4 unmasks β2-adrenoceptor-mediated inotropic and lusitropic effects in the left but not right ventricular myocardium of rat.
abstract: Cyclic nucleotide phosphodiesterase (PDE)3 and PDE4 provide the major PDE activity in cardiac myocytes and shape β1-adrenoceptor-dependent cardiac cAMP signaling but their role in regulating β2-adrenoceptor-mediated responses is less well known. We investigated potential differences in PDE3 and PDE4 activities between right (RV) and left (LV) ventricular myocardium, and their role in regulating β2-adrenoceptor effects. PDE3 activity in the microsomal fraction was lower in RV than in LV but was the same in the cytosolic fraction. However, no significant difference between RV and LV was found when the PDE4 activity was studied. β2-adrenoceptor activation increased inotropism and lusitropism in LV when measured in the presence of either the PDE3 inhibitor cilostamide, the PDE4 inhibitor rolipram or a non-selective PDE inhibitor IBMX. However, the joint inhibition of both PDE3 and PDE4 was necessary in RV to uncover β2-adrenoceptor-induced inotropic and lusitropic effects. Our results indicate different regulation of β2-adrenoceptor-mediated contractility by PDE3 and PDE4 in RV and LV of the rat heart. In the case of PDE3 due to a different contribution of the enzyme in the microsomal fraction whereas in the case of PDE4 it can be attributed to differences in the intracellular distribution and coupling to β2-adrenoceptors.
authors.affiliation: Department of Biochemistry and Molecular Biology A, University of Murcia, 30100 Murcia, Spain. Electronic address: fsoler@um.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Soler
authors.affiliation: Department of Biochemistry and Molecular Biology A, University of Murcia, 30100 Murcia, Spain. Electronic address: fbelda@um.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Belda
authors.affiliation: School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK. Electronic address: jpschi@gmail.com.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pérez-Schindler
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain. Electronic address: jehernca@um.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Hernández-Cascales
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology; D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D018343:Receptors, Adrenergic, beta-2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517290:Pde3a protein, rat; C521385:Pde4a protein, rat
keywords: Inotropy; Interventricular difference; Lusitropy; PDE3-4 activities; β(2)-adrenoceptor activation