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Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

¹Department of Cardiology and Angiology and ²Institute for Pharmacology and Toxicology, University Hospital Münster, D-48129 Münster; ³Institute for Pathology, University of Essen, D-45122 Essen, Germany; and ⁴Department of Pediatrics and Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908-1356

Submitted 2 December 2002 ; accepted in final form 2 February 2003

To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with cardiac-specific overexpression of the A₁ adenosine receptor (A₁AR). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity: 437 ± 18 vs. 522 ± 24 beats/min, P < 0.05; exercise: 650 ± 13 vs. 765 ± 28 beats/min, P < 0.05; 1 h after exercise: 588 ± 18 vs. 720 ± 12 beats/min, P < 0.05; all values are means ± SE). Mean HR was lower during exercise (589 ± 16 vs. 698 ± 34 beats/min, P < 0.05) and after exercise (495 ± 16 vs. 592 ± 27 beats/min, P < 0.05). Minimal HR was not different between genotypes. HR variability (SD of RR intervals) was reduced by 30% (P < 0.05) in TG compared with WT mice. Pertussis toxin (n = 4 pairs, 150 µg/kg ip) reversed bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ interval: 42 ± 2 vs. 37 ± 2 ms, P < 0.05), which was diminished but not abolished by pertussis toxin. Isolated Langendorff-perfused TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9 WT mice, P < 0.05). In conclusion, A₁AR regulate sinus nodal and AV nodal function in the mammalian heart in vivo. Enhanced expression of A₁AR causes sinus nodal and AV nodal dysfunction and supraventricular arrhythmias.

heart rate regulation; autonomous nervous system; heart rate variability; sinus node dysfunction; atrioventricular block; atrial fibrillation

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