Key result
Transgenic mice overexpressing the A1 adenosine receptor had significantly lower maximal heart rates during normal activity compared to wild-type mice (437 vs 522 beats/min, P<0.05).
Cardiac-specific overexpression of A1 adenosine receptors in mice causes sinus and AV nodal dysfunction and supraventricular arrhythmias, demonstrating their regulatory role in vivo.
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Suggests a mechanistic link between A1 adenosine receptor upregulation and chronotropic incompetence; leaves.
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 microg/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.
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Kirchhof et al. (2003) studied this question. Cardiac-specific overexpression of the A1 adenosine receptor vs. Wild-type mice was evaluated on Maximal heart rate during normal activity (beats/min) (p=<0.05). Transgenic mice overexpressing the A1 adenosine receptor had significantly lower maximal heart rates during normal activity compared to wild-type mice (437 vs 522 beats/min, P<0.05).
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