ryanodine and Bradycardia

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.

Topics: Analysis of Variance; Animals; Bradycardia; Calcium; Cardiotonic Agents; Dogs; Heart Atria; Isoproterenol; Membrane Potentials; Pyrimidines; Ryanodine; Tachycardia

To investigate the basis of ischemia-induced bradycardia (<60 beats/min), we isolated pacemaker cells from the rabbit sinoatrial node and exposed them to ischemic-like conditions, including omission of glucose, pH 6.6, and either 5.4 or 10 mM KCl to evaluate the role of increased serum [K]. A perforated-patch technique was employed to test the hypothesis that the arrhythmia is caused by attenuation of inward currents that contribute to the diastolic depolarization. After exposure to "ischemic" Tyrode containing 5.4 mM KCl, the pacemaker cells exhibited 13% slower beat rates and action potentials with 6-mV greater overshoots and 44% longer durations. In contrast, after exposure to "ischemic" Tyrode containing 10 mM KCl, the pacemaker cells exhibited a 7-mV depolarization of the maximum diastolic potential but no significant change in the overshoot. Beat rates were slowed by 43%, and the action potentials were prolonged by 46%. "Ischemic" Tyrode containing 5.4 mM KCl increased L-type Ca current, decreased T-type Ca current and reduced Ni-sensitive inward current tails (presumably Na-Ca exchange current), even after treatment with 40 muM ryanodine to block Ca release from the sarcoplasmic reticulum. "Ischemic" Tyrode containing 10 mM KCl increased hyperpolarization-activated inward current at diastolic potentials and reduced the slowly activating component, but not the rapidly activating component, of delayed rectifier K current. Our results suggest that reductions of inward Na-Ca exchange current and T-type Ca current contribute to "ischemia"-induced "bradycardia" in sinoatrial node pacemaker cells.

Topics: Action Potentials; Animals; Bradycardia; Calcium; Cell Hypoxia; Isotonic Solutions; Rabbits; Ryanodine; Sarcoplasmic Reticulum; Sinoatrial Node

Topics: Action Potentials; Animals; Bradycardia; Calcium; Cell Hypoxia; Isotonic Solutions; Rabbits; Ryanodine; Sarcoplasmic Reticulum; Sinoatrial Node