Effects of adenosine A1-receptor activation on torsade de pointes in rabbits.
OBJECTIVE
We tested whether the adenosine A1 receptor agonist, R-PIA, suppressed torsade de pointes (TdP) induced by the delayed rectifier potassium channel blocker clofilium. Furthermore, we studied the underlying mechanism: beta-adrenergic antagonism or ATP-sensitive K+ channel (IK-ATP) opening.


METHODS
In anesthetized rabbits, TdP was induced by simultaneous infusion of clofilium and the alpha1-adrenoceptor agonist methoxamine. Four groups were studied: (1) saline infusion after TdP induction; (2) R-PIA (1.3 mg/kg) infusion; (3) R-PIA infusion after propranolol (2 micromol/kg) pretreatment; (4) R-PIA infusion after glibenclamide (10 micromol/kg) pretreatment.


RESULTS
TdP suppression rate was 0% in group 1, 78% in group 2 (p<0.01 vs. group 1), 67% in group 3 (p<0.05 vs. group 1, p = NS vs. group 2), 33% in group 4 (p = NS vs. group 1, p = 0.08 vs. group 2). TdP induction coincided with increased QT/QTc duration and QT dispersion. TdP suppression coincided with reduced QT dispersion, but further QT/QTc lengthening.


CONCLUSIONS
R-PIA suppressed TdP, not by beta-adrenergic antagonism, but mostly by IK-ATP opening. QT dispersion correlated better with TdP induction/suppression than QT/QTc duration.
Tan
H L
HL
Cardiac Electrophysiology and Arrhythmia Service, Stanford University Medical Center, California 94305, USA.
Hou
C J
CJ
Sung
R J
RJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D008729:Methoxamine / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000037:antagonists & inhibitors; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced / Q000188:drug therapy*
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D018696:Neuroprotective Agents; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; C047235:N-(1-methyl-2-phenylethyl)adenosine; C022799:clofilium; D011433:Propranolol; D008729:Methoxamine; D000241:Adenosine