The increase in rat ventricular automaticity induced by salbutamol is mediated through β1- but not β2-adrenoceptors: Role of phosphodiesterases

AimsWhile β2-adrenoceptor (AR) agonists are useful bronchodilators, they also produce cardiac arrhythmias. These agents are not fully selective and also activate β1-AR, but the involvement of β1-AR and β2-AR in the observed pro-arrhythmic effect has not been established. We studied the effect of β1-AR and β2-AR activation on ventricular automaticity and the role of phosphodiesterases (PDE) in regulating this effect.Main methodsExperiments were performed in the spontaneously beating isolated right ventricle of the rat heart. We also measured cAMP production in this tissue.Key findingsThe β2-AR agonist salbutamol (1-100 μM) produced a concentration-dependent increase in ventricular automaticity that was not affected by 50 nM of the β2-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 β1-AR antagonist CGP20712A. 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.SignificanceThese results indicate that the increase of ventricular automaticity elicited by salbutamol was exclusively mediated through β1-AR and enhanced by non-selective PDE inhibition with theophylline or selective PDE4 inhibition. However, PDE3 did not appear to regulate this effect.