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1 Department of Cardiology and Angiology, University Hospital Muenster, Muenster, Germany
2 Institute for Pharmacology and Toxicology, University Hospital Muenster, Muenster, Germany
3 Department of Pediatrics and Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: kirchhp{at}uni-muenster.de.
To investigate whether an altered function of adenosine receptors could contribute to sinus node or AV dysfunction in conscious mammals, we studied mice with cardiac-specific overexpression of the A1 adenosine receptor (TG). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 minutes swimming), and 1 hr after exercise. TG mice had lower maximal heart rate than WT (HR, normal activity: 437±18 vs. 522±24*, exercise: 650±13 vs. 765±28*, after exercise: 588±18 vs. 720±12*, all values in beats/min as mean ± SEM, *: p<0.05). Mean HR was lower during exercise (589±16 vs. 698±34*) and after exercise (495±16 vs. 592±27*). Minimal HR was not different between genotypes. HR variability (standard deviation of RR intervals) was reduced by 30%* in TG compared to WT. Pertussis toxin (n=4 pairs, 150µg/kg intraperitonally applied) reversed bradycardia after 48 hrs. TG mice showed first degree AV nodal block (PQ interval 42±2ms vs. 37±2ms*), which was diminished but not abolished by pertussis toxin. Isolated Langendorff-perfused TG hearts developed spontaneous atrial arrhythmias (3/6 TG vs. 0/9 WT*). In conclusion, A1AR regulate sinus nodal and AV nodal function in the mammalian heartin vivo. Enhanced expression of A1AR causes sinus nodal and AV nodal dysfunction, and supraventricular arrhythmias.
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