Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor.
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.
Kirchhof
Paulus
P
Department of Cardiology and Angiology, University Hospital Münster, D-48129 Münster, Germany. kirchhp@uni-muenster.de
Fabritz
Larissa
L
Fortmuller
Lisa
L
Matherne
G Paul
GP
Lankford
Amy
A
Baba
Hideo A
HA
Schmitz
Wilhelm
W
Breithardt
Gunter
G
Neumann
Joachim
J
Boknik
Peter
P
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
D009124:Muscle Proteins; D018047:Receptors, Purinergic P1; D037342:Pertussis Toxin