AIMS: To investigate the role of beta receptor blockade via adenosine A(1) receptor stimulation on amitriptyline-induced QRS prolongation. METHODS: Isolated rat hearts were randomized into three groups (n=8 for each group). After pretreatment with 5% dextrose (control) or DPCPX (8-cyclopentyl-1,3-dipropylxanthine), or propranolol + DPCPX, amitriptyline infusion was given to all groups. Intact beta adrenergic receptor response was verified with a bolus dose of isoproteranol (3 x 10(-5)M). RESULTS: Amitriptyline (5.5 x 10(-5)M) infusion following pretreatment with 5% dextrose or 10(-4)M DPCPX prolonged QRS by 40-110% and 30-75%, respectively. After the beta receptor blockade with 10(-2)M propranolol bolus, amitriptyline infusion following pretreatment with DPCPX prolonged QRS by 40-130%. Amitriptyline infusion following pretreatment with DPCPX (10(-4)M) shortened the QRS at 40, 50 and 60 min significantly when compared to propranolol+DPCPX group (168.8+/-4.9%, p<0.05; 170.8+/-6.9%, p<0.01; 174.0+/-6.9%, p<0.01, respectively). Amitriptyline infusion following pretreatment with 5% dextrose prolonged QRS duration significantly at 50th minutes (209.5+/-6.1%, p<0.05) compared to DPCPX pretreatment group. CONCLUSION: DPCPX pretreatment shortened amitriptyline-induced QRS prolongation. Beta adrenergic receptor blockade enhanced QRS prolongation shortened by DPCPX pretreatment. Adenosine A(1) receptor stimulation related to beta adrenergic receptor blockade may play a role in amitriptyline-induced QRS prolongation in isolated rat hearts.