title: The phosphodiesterase 3 inhibitor cilostamide enhances inotropic responses to glucagon but not to dobutamine in rat ventricular myocardium.
abstract: The effects of phosphodiesterase (PDE) inhibitors (1-3) on tissue cAMP concentrations and the inotropic responses to dobutamine and glucagon were investigated in electrically driven right ventricular strips of the rat heart. Dobutamine (0.3-100 microM) produced a concentration-dependent positive inotropic effect which was not affected by 50 nM (+/-)-1-(2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy)-3-((1-methylethyl)amino)-2-butanol hydrochloride (ICI 118551), a beta2-receptor antagonist, but was virtually abolished by 0.3 microM (+/-)-2-hydroxy-5-(2-((2-hydroxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-l)phenoxy)propyl)amino)ethoxy)-benzamide methanesulfonate (CGP 20712A), a beta1-receptor antagonist. Glucagon (0.01-1 microM) also enhanced the contractility of the preparation in a concentration-dependent way. Selective inhibitors of PDE 1 8-methoxymethyl-3-isobutyl-1-methylxantine (MIMX, 1 muM), PDE 2 erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA, 1 microM) and PDE 3 cilostamide (0.1 microM) did not affect basal contractility. Cilostamide increased the positive inotropic effects of glucagon but not those of dobutamine. MIMX and EHNA did not alter the effects of either dobutamine or glucagon. Dobutamine (3 microM), but not glucagon (0.1 microM), increased tissue levels of cAMP. 1 microM of MIMX or EHNA were devoid of effects and failed to alter the effects of dobutamine and glucagon on cAMP. Cilostamide (0.1 microM) did not increase the effects of dobutamine but caused glucagon to enhance cAMP. The pharmacological and biochemical data presented in this study can be explained quantitatively by a cell compartment model in which PDE 3 appears to be colocalized with the contractile machinery responsible for the effects of glucagon but not those of dobutamine. Neither PDE 1 nor PDE 2 appears to regulate the inotropic effects of dobutamine and glucagon in rat ventricular myocardium.
authors.affiliation: Departmento de Farmacologia, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Juan-Fita
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Vargas
authors.forename: Jesús
authors.initials: J
authors.lastname: Hernández
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004280:Dobutamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005092:Exonucleases / Q000037:antagonists & inhibitors; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function; D014970:Xanthines / Q000494:pharmacology
chemical_list: C119531:8-methoxymethyl-3-isobutyl-1-methylxanthine; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D015363:Quinolones; D014970:Xanthines; D004280:Dobutamine; C021294:cilostamide; C010192:9-(2-hydroxy-3-nonyl)adenine; D005934:Glucagon; C051360:1,3-dipropyl-8-cyclopentylxanthine; C049763:CGP 20712A; D000242:Cyclic AMP; D005092:Exonucleases; C022650:spleen exonuclease; D043264:Phosphodiesterase I; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000225:Adenine