ATP SHORTENS ATRIAL ACTION-POTENTIAL DURATION IN THE DOG - ROLE OF ADENOSINE, THE VAGUS NERVE, AND G-PROTEIN

The mechanism by which adenosine 5'-triphosphate (ATP) shortens atrial action potential duration was studied in a canine model in vivo. Prev ious studies have indicated that the negative chronotropic and dromotr opic actions of ATP in the canine heart are mediated by a vagal reflex and by adenosine. However, the mechanism of ATP's action on atrial ac tion potential duration remains unknown. The effects of ATP on endocar dial monophasic action potential were determined under baseline condit ions (control) and after left cervical vagotomy followed by right vagu s nerve afferent blockade with capsaicin (1% in olive oil), and subseq uent bilateral cervical vagotomy plus propranolol (1.0 mg/kg, i.v.). I n addition, the effects of ATP and adenosine were determined 48 h foll owing the administration of pertussis toxin (PTX, 30 mu g/kg, i.v.). P TX intoxication was verified by monitoring plasma levels of insulin du ring glucose tolerance tests. ATP (4 and 6 mu mol/kg, rapid bolus into right atrium) markedly shortened right atrial action potential durati on at 50% repolarization (APD(50)) from 101 +/- 8 to 22 +/- 6 and from 111 +/- 8 to 14 +/- 2 ms, respectively. Adenosine (equimolar doses gi ven in an identical mode) had a smaller effect, i.e., APD(50) of 106 /- 8 and 109 +/- 6 was shortened to 77 +/- 12 and 76 +/- 12 ms, respec tively. Left cervical vagotomy slightly reduced the effect of ATP but not that of adenosine. Blockade of right vagal C fiber afferent traffi c using local application of capsaicin to the right cervical vagosympa thetic trunk markedly attenuated the effect of ATP, but not that of ad enosine. Autonomic blockade (i.e., bilateral cervical vagotomy and pro pranolol) markedly attenuated the effect of ATP, but not of adenosine; for example, the effect of ATP (6 mu mol/kg) was reduced from 86 +/- 2% shortening of APD(50) to 24 +/- 5% (p < 0.05), while that of adenos ine was 32 +/- 8 and 20 +/- 4% (ns) before and after autonomic blockad e, respectively. Treatment with PTX completely abolished the effect of both ATP and adenosine on atrial action potential duration. These dat a indicate that (i) the effect of ATP on the canine atrial action pote ntial duration is mediated to a large extent by a vagal reflex trigger ed by the nucleotide and to a lesser extent by adenosine, the product of ATP's enzymatic degradation, (ii) the afferent traffic of this refl ex travels mainly via the right vagal C fibers, and (iii) the effects of both the vagal and the adenosine components are mediated by PIX-sen sitive guanine nucleotide binding proteins (G proteins) coupled to the muscarinic cholinergic receptors and A(1) adenosine receptors, respec tively.