Adenosine A1 Receptor Activation Suppresses Torsade De Pointes by Opening ATP Sensitive K+ Channels in Rabbits

Background: Torsade de pointes (TDP) is thought to result from early afterdepolarizations (EADs). Although it has been shown that adenosine can suppress catecholamine-induced EADs in isolated guine pig ventricular myocytes, its effects on TDP in vivo are uncertain. Methods: TDP was induced in 25 anesthetized rabbits weighing 3-4 kg by simultaneous intravenous infusion of methoxamine, an α1-adrenoceptor agonist (70 nmol/kg/min), and clofilium, blocker of the delayed rectifier K+ channel (76 nmol/kg/min). After TDP was initiated, saline (n = 6) or the adenosine A1 receptor agonist R-phenylisopropyladenosine (R-PIA, 1.3 mg/kg, N = 6) was infused. Two additional groups were pretreated with propranolol (2 μmol/kg, N = 7), β-adrenoceptor blocker, or glibenclamide (10 μmol/kg, N = 6), an ATP sensitive K+ channel (IK-ATP) blocker, prior to R-PI infusion. Results: Suppression of TDP in the R-PI and the R-PIA/propranolol groups was not associated with shortening of the QT interval (baseline: 205 ± 9 ms, onset of TDP: 344 ± 10 ms, after suppression of TDP: 400 ± 40 ms [p < NS vs onset of TDP], mean ± SD), but with reduction of QT interval dispersion (2.7 ± 0.5%, 7.5 ± 1.1%, and 4.2 ± 0.7% [p < 0.05 vs onset of TDP], respectively), as measured from 6 limb leads. Conclusion: Adenosine A1 receptor activation suppresses TDP induced by K+ channel blockade primarily by opening IK-ATP, rather than by antagonizing β-adrenoceptor mediated mechanisms. This effect is associated with reduced QT interval dispersion, but not with QT interval shortening.