Tachybradycardia in the isolated canine right atrium induced by chronic sympathetic stimulation and pacemaker current inhibition.
The mechanisms of sinoatrial node (SAN) dysfunction in patients with chronically elevated sympathetic tone and reduced pacemaker current (I(f); such as heart failure) are poorly understood. We simultaneously mapped membrane potential and intracellular Ca(2+) in the Langendorff-perfused canine right atrium (RA). Blockade of either I(f) (ZD-7288) or sarcoplasmic reticulum Ca(2+) release (ryanodine) alone decreased heart rate by 8% (n = 3) and 16% (n = 3), respectively. Combined treatment of ZD-7288 and ryanodine consistently resulted in prolonged (> or =3 s) sinus pauses (PSPs) (n = 4). However, the middle SAN remained as the leading pacemaking site after these treatments. Prolonged exposure with isoproterenol (0.01 micromol/l) followed by ZD-7288 completely suppressed SAN but triggered recurrent ectopic atrial tachycardia. Cessation of tachycardia was followed by PSPs in five of eight RAs. Isoproterenol initially increased heart rate by 75% from baseline with late diastolic intracellular Ca(2+) elevation (LDCAE) from the superior SAN. However, after a prolonged isoproterenol infusion, LDCAE disappeared in the superior SAN, the leading pacemaker shifted to the inferior SAN, and the rate reduced to 52% above baseline. Caffeine (2 ml, 20 mmol/l) injection after a prolonged isoproterenol infusion produced LDCAE in the SAN and accelerated the SAN rate, ruling out sarcoplasmic reticulum Ca(2+) depletion as a cause of Ca(2+) clock malfunction. We conclude that in an isolated canine RA preparation, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the RA, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Combined malfunction of both membrane and Ca(2+) clocks underlies the mechanisms of PSPs.
Joung
Boyoung
B
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University Schoolof Medicine, Indianapolis, Indiana 46202, USA.
Shinohara
Tetsuji
T
Zhang
Hong
H
Kim
Daehyeok
D
Choi
Eue-Keun
EK
On
Yong-Keun
YK
Piccirillo
Gianfranco
G
Chen
Peng-Sheng
PS
Lin
Shien-Fong
SF
D000704:Analysis of Variance; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology*
D002316:Cardiotonic Agents; D011743:Pyrimidines; C082246:ICI D2788; D012433:Ryanodine; D007545:Isoproterenol; D002118:Calcium