Sudden cardiac death syndrome, following coronary occlusion and acute myocardial ischemia, is a leading cause of mortality in adults in the U.S. During the first 24 hours of ischemia, the infarct zone slowly expands in the territory of the occluded artery, and serious cardiac arrhythmias leading to death can occur. These arrhythmias probably are caused by (a) """"""""low potential automaticity"""""""" that occurs in """"""""endocardial border zone"""""""" Purkinje fibers with maximum diastolic potentials < or = - 60 mV, or (b) triggered activity in ventricular muscle cells on the epicardial or lateral borders of the infarct. Here, we will study the pharmacology of models of this low potential automaticity and triggering using standard microelectrode techniques. We will also study the effects of antiarrhythmic drugs on catecholamine-enhanced automaticity occurring at both the high and low levels of maximum diastolic potential (i.e., about - 90 mV and -55 mV, respectively). Such catecholamine- enhanced automaticity must also contribute to the infarct arrhythmias. These studies should help to explain the effects of antiarrhythmic drugs on tachycardias associated with myocardial infarction, and may explain why some tachycardias are resistant to drug therapy. We will also carry out experiments using current clamp techniques to characterize the voltage dependence of drug effects on high potential automaticity (which occurs from maximum diastolic potentials > -80 mV), intermediate potential automaticity (which occurs from maximum diastolic potentials of -61 to -70 mV) and low potential automaticity in barium- or cesium- pretreated Purkinje fibers. Finally, we will also use enzymatically- isolated single Purkinje cells and Purkinje cell clusters to investigate fluctuations of cleft K+ concentration ([K+]c), and or intracellular Ca++ activity ([CA++]i), during automaticity. These single cell/cell cluster experiments should permit us to determine whether time-dependent decreases of g R, sufficient to explain phase 4 depolarization, occur as a consequence of progressive declines of [K+]c and [Ca++]i during diastole.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL024354-10A1
Application #
3337638
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1979-08-01
Project End
1993-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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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