title: Metabolic effects of newly synthesized phosphodiesterase-3 inhibitor 6-[4-(4-methylpiperidin-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one on rat adipocytes.
abstract: BACKGROUND
  Clinical use of selective PDE3 inhibitors as cardiotonic agents is limited because of their chronotropic and lipolytic side effects. In our previous work, we synthesized a new PDE3 inhibitor named MC2 (6-[4-(4-methylpiperidin-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one) which produced a high positive inotropic action with a negative chronotropic effect. This work was done to evaluate the effects of MC2 on adipocytes and compare its effects with those of amrinone and cilostamide.
  
  
  METHODS
  Preadipocytes were isolated from rat adipose tissue and differentiated to adipocyte in the presence of cilostamide, amrinone or MC2. Lipolysis and adipogenesis was evaluated by measuring glycerol level and Oil Red O staining, respectively. Adipocyte proliferation and apoptosis were determined with MTT assay and Annexin V/PI staining, respectively.
  
  
  RESULTS
  Differentiation to adipocyte was induced by amrinone but not by cilostamide or MC2. Basal and isoproterenol-stimulated lipolysis significantly increased by cilostamide (p<0.05). Similarly, amrinone enhanced the stimulated lipolysis (p<0.01). On the other hand, MC2 significantly decreased both adipogenesis (p<0.05) and stimulated lipolysis (p<0.001). Also, incubation of differentiated adipocytes with MC2 caused the loss of cell viability, which was associated with the elevation in apoptotic rate (p<0.05).
  
  
  CONCLUSIONS
  Our data indicate that selective PDE3 inhibitors produce differential effects on adipogenesis and lipolysis. MC2 has proapoptotic and antilipolytic effects on adipocytes and does not stimulate adipogenesis. Therefore, in comparison with the clinically available selective PDE3 inhibitors, MC2 has lowest metabolic side effects and might be a good candidate for treatment of congestive heart failure.
authors.affiliation: Department of Pharmacology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. alinejadb861@mums.ac.ir.
authors.forename: Bagher
authors.initials: B
authors.lastname: Alinejad
authors.affiliation: Department of Pharmacology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Shafieer@mums.ac.ir.|Pharmacological Research Center of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Shafieer@mums.ac.ir.
authors.forename: Reza
authors.initials: R
authors.lastname: Shafiee-Nick
authors.affiliation: Department of laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran. Sadeghianh@mums.ac.ir.
authors.forename: Hamid
authors.initials: H
authors.lastname: Sadeghian
authors.affiliation: Pharmacological Research Center of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. ghorbania@mums.ac.ir.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Ghorbani
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C000604162:6-(4-(4-methylpiperidin-1-yl)-4-oxobutoxy)-4-methylquinolin-2(1H)-one; D058987:Phosphodiesterase 3 Inhibitors; D010880:Piperidines; D015363:Quinolones; C021294:cilostamide