We propose to use standard microelectrode techniques to study the electrophysiology and pharmacology of spontaneous impulse initiation in partially depolarized canine Purkinje fibers and myocardium. Abnormal automaticity will be induced in isolated Purkinje fibers and ventricular muscle preparations by current clamp depolarization techniques, or by depolarization with barium chloride, cesium chloride or palmityl carnitine. Triggered activity from early afterdepolarizations will be induced in Purkinje fibers with N-acetyl procainamide or cibenzoline. The response of both types of abnormal impulses will be studied with standard stimulation protocols, including intracellular current pulses, and will be compared to the results obtained from analogous studies on automaticity in normal Purkinje fibers. We will study the effects of standard and experimental antiarrhythmic drugs on these experimental models of abnormal automaticity. We will carry out parallel studies on the effects of these drugs on similar types of abnormal automaticity that occur in pathological canine (15-30 hr infarct zone Purkinje fiber) or feline cardiac tissues. Drug studies will also be carried out on triggered activity in infarct zone preparations when this is encountered. We will try to develop a model of """"""""current of injury"""""""" induced abnormal automaticity, as may occur during acute ischemia. These studies should give us insights into the electrophysiological mechanisms of cardiac arrhythmias, and may lead to improved, and perhaps rational, pharmacotherapy. If possible, we will extend extracellular unipolar recording techniques to detect electrical activity from the endocardial surface of the in situ canine ventricle: 1. to detect early afterdepolarizations and triggered activity in hearts made arrhythmic with N-acetyl procainamide, and 2. to detect activity during VPDs during the 24-hour arrhythmias occurring after coronary ligation, to demonstrate the presence of abnormal automaticity or triggered (EAD or DAD) activity.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pharmacology A Study Section (PHRA)
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Columbia University (N.Y.)
Schools of Medicine
New York
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Dangman, K H; Ziam, S; Miura, D S (1989) Local anesthetic and negative chronotropic effects of diltiazem on canine cardiac Purkinje fibers. Am Heart J 117:1271-7
Zaim, S; Dangman, K H (1989) Cellular electrophysiology and beta-adrenergic-blocking activity of dilevalol, the R,R-isomer of labetalol, on isolated canine cardiac tissues. J Cardiovasc Pharmacol 14:496-501
Dangman, K H (1988) Effects of procainamide on automatic and triggered impulse initiation in isolated preparations of canine cardiac Purkinje fibers. J Cardiovasc Pharmacol 12:78-87
Dangman, K H; Dresdner Jr, K P; Michler, R E (1988) Transmembrane action potentials and intracellular potassium activity of baboon cardiac tissues. Cardiovasc Res 22:204-12
Dangman, K H; Dresdner Jr, K P; Zaim, S (1988) Automatic and triggered impulse initiation in canine subepicardial ventricular muscle cells from border zones of 24-hour transmural infarcts. New mechanisms for malignant cardiac arrhythmias? Circulation 78:1020-30
Dangman, K H; Miura, D S (1987) Does if control normal automatic rate in canine cardiac Purkinje fibers? Studies on the negative chronotropic effects of lidoflazine. J Cardiovasc Pharmacol 10:332-40
Dangman, K H; Wang, H H; Reynolds, R D (1986) Studies on bethanidine and meobentine: direct and indirect effects of antifibrillatory drugs. J Cardiovasc Pharmacol 8:1185-94
Hoffman, B F; Dangman, K H (1986) The role of antiarrhythmic drugs in sudden cardiac death. J Am Coll Cardiol 8:104A-109A
Dangman, K H; Miura, D S (1985) Electrophysiological effects of bethanidine sulfate on canine cardiac Purkinje fibers and ventricular muscle cells. J Cardiovasc Pharmacol 7:50-8
Dangman, K H (1985) Effects of bepridil on transmembrane action potentials recorded from isolated canine cardiac tissues. Studies on normal and infarct-zone Purkinje fibres and ventricular muscle cells. Naunyn Schmiedebergs Arch Pharmacol 329:326-32

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