title: The increase in rat ventricular automaticity induced by salbutamol is mediated through β(1)- but not β(2)-adrenoceptors: role of phosphodiesterases.
abstract: OBJECTIVE
  While β(2)-adrenoceptor (AR) agonists are useful bronchodilators, they also produce cardiac arrhythmias. These agents are not fully selective and also activate β(1)-AR, but the involvement of β(1)-AR and β(2)-AR in the observed pro-arrhythmic effect has not been established. We studied the effect of β(1)-AR and β(2)-AR activation on ventricular automaticity and the role of phosphodiesterases (PDE) in regulating this effect.
  
  
  METHODS
  Experiments were performed in the spontaneously beating isolated right ventricle of the rat heart. We also measured cAMP production in this tissue.
  
  
  RESULTS
  The β(2)-AR agonist salbutamol (1-100 μM) produced a concentration-dependent increase in ventricular automaticity that was not affected by 50nM of the β(2)-AR antagonist ICI 118551. This effect was enhanced by the non-selective PDE inhibitor theophylline (100 μM) and by the selective PDE4 inhibitors rolipram (1 μM) and Ro 201724 (2 μM), but not modified by the selective PDE3 inhibitors cilostamide (0.3 μM) or milrinone (0.2 μM). The effects of salbutamol alone and in the presence of either theophylline or rolipram were virtually abolished by 0.1 μM β(1)-AR antagonist CGP 20712A. Salbutamol (10 μM) increased the cAMP concentration, and this effect was abolished by CGP 20712A (0.1 μM) but enhanced by theophylline (100 μM) or rolipram (1 μM). Cilostamide (0.3 μM) failed to modify the effect of salbutamol on cAMP concentration.
  
  
  CONCLUSIONS
  These results indicate that the increase of ventricular automaticity elicited by salbutamol was exclusively mediated through β(1)-AR and enhanced by non-selective PDE inhibition with theophylline or selective PDE4 inhibition. However, PDE3 did not appear to regulate this effect.
authors.affiliation: Department of Pharmacology, Medical School and Unit of Radiopharmacy, University Hospital Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gonzalez-Muñoz
authors.forename: Teodomiro
authors.initials: T
authors.lastname: Fuente
authors.forename: Santiago
authors.initials: S
authors.lastname: Medin-Aguerre
authors.forename: Jesús
authors.initials: J
authors.lastname: Hernández-Cascales
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D010726:Phosphodiesterase Inhibitors; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D013806:Theophylline; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000420:Albuterol