title: Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor.
abstract: 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.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Münster, D-48129 Münster, Germany. kirchhp@uni-muenster.de
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Lisa
authors.initials: L
authors.lastname: Fortmuller
authors.forename: G Paul
authors.initials: GP
authors.lastname: Matherne
authors.forename: Amy
authors.initials: A
authors.lastname: Lankford
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.forename: Gunter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
authors.forename: Peter
authors.initials: P
authors.lastname: Boknik
mesh_terms: D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology*; D013686:Telemetry
chemical_list: D009124:Muscle Proteins; D018047:Receptors, Purinergic P1; D037342:Pertussis Toxin