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Electrophysiologic basis of procainamide therapeutic and toxic effects on ischemia-related reentrant ventricular arrhythmias
ABSTRACTS
ELECTROPHYSIOLOGIC BASIS OF PROCAINAMIDE THERAPEUTIC AND TOXIC EFFECTS ON ISCHEMIA-RELATED REENTRANT VENTRICULAR ARRHYTHMIAS Nabil Ei-Sherif, MD, FACC; Veterans Administration H--ospital and Downstate School of Medicine, Brooklyn, NY Reentrant ventricular arrhythmias (RVA) were analyzed in 15 dogs 3-5 days following ligation of the anterior descending coronary artery utilizing averaged 'composite' recordings of the electrical activity of reentrant pathways (RP) from the epicardial surface of the infarction zone (IZ). Procainamide (P) was given as an IV bolus over 3 min. in doses of 5, i0, or 15 mg/Kg. In a dose-related response, P resulted in smooth widening of normal zone electrograms and surface QRS (5-60%) but marked fractionation, delay and/or block of IZ electrograms. P(10 mg/Kg) abolished spontaneous RVA and RVA initiated by premature beats (PBs). This was associated with conduction block in the RP and was usually preceded by evidence of conduction delay in RP resulting in gradual increase of coupling of extrasystolic beats and slowing of the rate ofventricular tachycardia. Prior to abolition of RVA initiated by PBs, p resulted in: i) narrowing of the reentry zone; 2) shift of the narrowed reentry zone to longer cardiac cycle lengths, and 3) lengthening of the coupling interval of the first reentrant beat. P(15mg/Kg) had a greater depressant effect on conduction that was markedly accentuated by rapid cardiac pacing (RCP). RCP initiated ventricular fibrillation (VF) in 7 of 15 dogs only following P(15mg/ Kg). We conclude that conduction in ischemic myocardium is more sensitive to P depressant effect. In a ' therapeutic' dose, P could abolish RVA due to block in RP while in a 'toxic' dose, it may increase the propensity to VF. This seems to be related to the development of greater fractionation of conduction in the IZ rather than complete block in RP.
ELECTROPHYSIOLOGIC INTERACTIONS OF BRETYLIUM TOSYLATE AND HYPOXIA ON CANINE PURKINJE FIBERS Masao Nishimura, MD; Yoshio Watanabe, MD, FACC, Cardiovascular Institute, Fujita-gakuen University, Toyoake, Aichi, Japan Electrophysiologic effects of bretylium tosylate(20mg/L) were studied on transmembrane action potentials of canine Purkinje fibers from normal and reserpine-pretreated dogs. Microelectrode impalement into the same fiber was maintained throughout the experiment. In 7 normal Purkinje fibers, bretylium prolonged action potential duration(APd) from 280 to 323 msec, but caused no change in action potential amplitude(APa), maximal diastolic potential(MDP) and dV/dt of phase O under normal oxygen concentration(95%O2+ 5%C02). In 6 normal Purkinje fibers, hypoxia(95%N2+5%CO 2) significantly decreased APa(127-~124mV), M D P ( 9 1 ~ 8 9 m V ) , dV/dt(518-)498V/sec) and APd(289-~263msec) at 30 min, and further caused a significant reduction of dV/dt(498-9490V/ sec) alone at 60 min. After a recovery from hypoxia, Purkinje fibers were again exposed to hypoxia for 60 min to study the interactions of bretylium and hypoxia. Bretylium added to the perfusate after 30 min of hypoxia significantly increased APa (122-~126mV) , MDP (88-990mV) and APd (264-~317msec) , and insignificantly improved dV/dt (4.93 -~508V/sec) against the expected greater reduction of dV/ dt at 60 min. The effects of bretylium were studied in 8 reserpine-pretreated Purkinje fibers in the same manner. Unlike in normal Purkinje fibers, bretylium d i d n o t reverse the effect of hypoxia on APa, MDP and dV/dt, but prolonged APd(246-~296msec)significantly. These results suggest that (1)antiarrhythmic effects of bretylium in h y p o x i c or depressed myocardium are probably ascribed to hyperpolarization, increased dV/dt of phase O and improved conduction, and (2)these electrophysiologic effects appear to depend on catecholamine release by bretylium.
EFFECTS OF AHR-2666 ON OUABAIN ~ N T O X I C A T E D CANINE CARDIAC PURKINJE FIBERS. Michael S. Siegal, MD, Brian F. Hoffman, MD, Columbia College of Physicians and Surgeons, New York, N.Y. We used standard microelectrode techniques to study the effects of "slow channel" blockade and increased [Ca2+]o on the electrophysiology of Ouabain (0)-intoxicated Purkinje fibers (PF). We have previously suggested that AHR-2666 [3-(m-chlorophen0xy)-l-methylcarbamoylpyrrolidine](0.18 - 0.24 mM) (AHR), a modifier of sarcotubular Ca 2+ movement in skeletal muscle, is also a reversible blocker isi, the inward current largely responsible for the PF action potential plateau. PF superfused for 35 minutes with Tyrode's solution containing 0 (2 x 10-7M) manifest Ca2+-dependent delayed after depolarizations (DAD) on termination of stimulation at a cycle length (CL) = 500 msec. We found that AHR (0.18 - 0.24 mM) reversibly suppresses DAD in 0-intoxicated PF (O-PF). Effects of AHR are in turn reversible by increasing [Ca++] o and/or returning to AHR-free superfusate. We found that in O-PF, resumption of stimulation at CL = 500 msec after several minutes of quiescence l e a d s t o progressive loss of maximum diastolic potential (MDP) during the first i0 seconds of stimulation, and that this loss of MDP is accentuated in the presence of elevated [ C a + + ] . AHR (0.24 mM) suppresses the 10ss of MDP on initiation of stimulation in O-PF. On cessation of stimulation at CL = 500 msec, MDP in O-PF slowly increases. This effect also is reversed in the presence of AHR (0.24 mM). These results suggest that "slow channel" blockade and /or changes in sarcotubular Ca 2+ stores may alter the electrophysiologic manifestations of 0 toxicity in PF.
TETRODOTOX!N EFFECTS ON DISEASED HUMAN ATRIUM. Alla_____n_n Herdof MD, Luc Mary-Rabine MD, James Malm MD FACC, Michael Rosen MD FACC, Columbia Univ., New York, NY Previous studies of the electrophysiology of diseased human atrial fibers (HAF) have indicated their electrical activity is modified primarily by blockers of the slow inward current, whereas normal fibers are more susceptable to the effects of agents that block the fast inward (sodium) current. The role of the fast inward current in diseased HAF has not been well delineated. We used standard microelectrode techniques to determine the effects of the fast channel blocker, tetrodotoxin (TTX) on the action potential (AP), phase 4 depolarization and delayed afterdepolarizations (DAD) in diseased HAF. Control AP characteristics of 8 diseased HAF were (M-+SE), amplitude 54.8+3.5 mV, maximum diastolic potential (MDP) -52.5+2.6 mY, activation voltage -42.9+2.2 mV. Control spontaneous rate was 26+3 beats/min and the slope of phase 4 depolarization was 4.0+1.5 mV/sec. The diseased HAF were superfused with TTX, .25-5.0 mg/l. There was a concentration dependent decrease in the slope of phase 4 and spontaneous rate. Significant decreases in AP amplitude and upstroke velocity occurred at TTX >0.5 mg/l and at TTX >I mg/l the fibers became i n excitable. Six fibers had DAD 18+4 mV in amplitude. TTX had no effect on the DAD. In comparison, our previous study showed that superfusion of diseased HAF with verapamil, 0. i mg/l, resulted in simultaneous decreases in AP amplitude, slope of phase 4, spontaneous rate and DAD amplitud~ At verapamil >0. i mg/l the fibers became inexcitable. This study indicates that in addition $o the slow inward current, there is a TTX sensitive Na current that contributes to the AP upstroke of diseased HAF. The TTX induced decreases in slope of phase 4 and spontaneous rate may reflect a diminution in resting conductance to sodium. However, DAD in HAF are not induced by a TTX sensitive current.
February 1979
The American Journal of CARDIOLOGY
Volume 43
429
ELECTROPHYSIOLOGIC BASIS OF PROCAINAMIDE THERAPEUTIC AND TOXIC EFFECTS ON ISCHEMIA-RELATED REENTRANT VENTRICULAR ARRHYTHMIAS Nabil Ei-Sherif, MD, FACC; Veterans Administration H--ospital and Downstate School of Medicine, Brooklyn, NY Reentrant ventricular arrhythmias (RVA) were analyzed in 15 dogs 3-5 days following ligation of the anterior descending coronary artery utilizing averaged 'composite' recordings of the electrical activity of reentrant pathways (RP) from the epicardial surface of the infarction zone (IZ). Procainamide (P) was given as an IV bolus over 3 min. in doses of 5, i0, or 15 mg/Kg. In a dose-related response, P resulted in smooth widening of normal zone electrograms and surface QRS (5-60%) but marked fractionation, delay and/or block of IZ electrograms. P(10 mg/Kg) abolished spontaneous RVA and RVA initiated by premature beats (PBs). This was associated with conduction block in the RP and was usually preceded by evidence of conduction delay in RP resulting in gradual increase of coupling of extrasystolic beats and slowing of the rate ofventricular tachycardia. Prior to abolition of RVA initiated by PBs, p resulted in: i) narrowing of the reentry zone; 2) shift of the narrowed reentry zone to longer cardiac cycle lengths, and 3) lengthening of the coupling interval of the first reentrant beat. P(15mg/Kg) had a greater depressant effect on conduction that was markedly accentuated by rapid cardiac pacing (RCP). RCP initiated ventricular fibrillation (VF) in 7 of 15 dogs only following P(15mg/ Kg). We conclude that conduction in ischemic myocardium is more sensitive to P depressant effect. In a ' therapeutic' dose, P could abolish RVA due to block in RP while in a 'toxic' dose, it may increase the propensity to VF. This seems to be related to the development of greater fractionation of conduction in the IZ rather than complete block in RP.
ELECTROPHYSIOLOGIC INTERACTIONS OF BRETYLIUM TOSYLATE AND HYPOXIA ON CANINE PURKINJE FIBERS Masao Nishimura, MD; Yoshio Watanabe, MD, FACC, Cardiovascular Institute, Fujita-gakuen University, Toyoake, Aichi, Japan Electrophysiologic effects of bretylium tosylate(20mg/L) were studied on transmembrane action potentials of canine Purkinje fibers from normal and reserpine-pretreated dogs. Microelectrode impalement into the same fiber was maintained throughout the experiment. In 7 normal Purkinje fibers, bretylium prolonged action potential duration(APd) from 280 to 323 msec, but caused no change in action potential amplitude(APa), maximal diastolic potential(MDP) and dV/dt of phase O under normal oxygen concentration(95%O2+ 5%C02). In 6 normal Purkinje fibers, hypoxia(95%N2+5%CO 2) significantly decreased APa(127-~124mV), M D P ( 9 1 ~ 8 9 m V ) , dV/dt(518-)498V/sec) and APd(289-~263msec) at 30 min, and further caused a significant reduction of dV/dt(498-9490V/ sec) alone at 60 min. After a recovery from hypoxia, Purkinje fibers were again exposed to hypoxia for 60 min to study the interactions of bretylium and hypoxia. Bretylium added to the perfusate after 30 min of hypoxia significantly increased APa (122-~126mV) , MDP (88-990mV) and APd (264-~317msec) , and insignificantly improved dV/dt (4.93 -~508V/sec) against the expected greater reduction of dV/ dt at 60 min. The effects of bretylium were studied in 8 reserpine-pretreated Purkinje fibers in the same manner. Unlike in normal Purkinje fibers, bretylium d i d n o t reverse the effect of hypoxia on APa, MDP and dV/dt, but prolonged APd(246-~296msec)significantly. These results suggest that (1)antiarrhythmic effects of bretylium in h y p o x i c or depressed myocardium are probably ascribed to hyperpolarization, increased dV/dt of phase O and improved conduction, and (2)these electrophysiologic effects appear to depend on catecholamine release by bretylium.
EFFECTS OF AHR-2666 ON OUABAIN ~ N T O X I C A T E D CANINE CARDIAC PURKINJE FIBERS. Michael S. Siegal, MD, Brian F. Hoffman, MD, Columbia College of Physicians and Surgeons, New York, N.Y. We used standard microelectrode techniques to study the effects of "slow channel" blockade and increased [Ca2+]o on the electrophysiology of Ouabain (0)-intoxicated Purkinje fibers (PF). We have previously suggested that AHR-2666 [3-(m-chlorophen0xy)-l-methylcarbamoylpyrrolidine](0.18 - 0.24 mM) (AHR), a modifier of sarcotubular Ca 2+ movement in skeletal muscle, is also a reversible blocker isi, the inward current largely responsible for the PF action potential plateau. PF superfused for 35 minutes with Tyrode's solution containing 0 (2 x 10-7M) manifest Ca2+-dependent delayed after depolarizations (DAD) on termination of stimulation at a cycle length (CL) = 500 msec. We found that AHR (0.18 - 0.24 mM) reversibly suppresses DAD in 0-intoxicated PF (O-PF). Effects of AHR are in turn reversible by increasing [Ca++] o and/or returning to AHR-free superfusate. We found that in O-PF, resumption of stimulation at CL = 500 msec after several minutes of quiescence l e a d s t o progressive loss of maximum diastolic potential (MDP) during the first i0 seconds of stimulation, and that this loss of MDP is accentuated in the presence of elevated [ C a + + ] . AHR (0.24 mM) suppresses the 10ss of MDP on initiation of stimulation in O-PF. On cessation of stimulation at CL = 500 msec, MDP in O-PF slowly increases. This effect also is reversed in the presence of AHR (0.24 mM). These results suggest that "slow channel" blockade and /or changes in sarcotubular Ca 2+ stores may alter the electrophysiologic manifestations of 0 toxicity in PF.
TETRODOTOX!N EFFECTS ON DISEASED HUMAN ATRIUM. Alla_____n_n Herdof MD, Luc Mary-Rabine MD, James Malm MD FACC, Michael Rosen MD FACC, Columbia Univ., New York, NY Previous studies of the electrophysiology of diseased human atrial fibers (HAF) have indicated their electrical activity is modified primarily by blockers of the slow inward current, whereas normal fibers are more susceptable to the effects of agents that block the fast inward (sodium) current. The role of the fast inward current in diseased HAF has not been well delineated. We used standard microelectrode techniques to determine the effects of the fast channel blocker, tetrodotoxin (TTX) on the action potential (AP), phase 4 depolarization and delayed afterdepolarizations (DAD) in diseased HAF. Control AP characteristics of 8 diseased HAF were (M-+SE), amplitude 54.8+3.5 mV, maximum diastolic potential (MDP) -52.5+2.6 mY, activation voltage -42.9+2.2 mV. Control spontaneous rate was 26+3 beats/min and the slope of phase 4 depolarization was 4.0+1.5 mV/sec. The diseased HAF were superfused with TTX, .25-5.0 mg/l. There was a concentration dependent decrease in the slope of phase 4 and spontaneous rate. Significant decreases in AP amplitude and upstroke velocity occurred at TTX >0.5 mg/l and at TTX >I mg/l the fibers became i n excitable. Six fibers had DAD 18+4 mV in amplitude. TTX had no effect on the DAD. In comparison, our previous study showed that superfusion of diseased HAF with verapamil, 0. i mg/l, resulted in simultaneous decreases in AP amplitude, slope of phase 4, spontaneous rate and DAD amplitud~ At verapamil >0. i mg/l the fibers became inexcitable. This study indicates that in addition $o the slow inward current, there is a TTX sensitive Na current that contributes to the AP upstroke of diseased HAF. The TTX induced decreases in slope of phase 4 and spontaneous rate may reflect a diminution in resting conductance to sodium. However, DAD in HAF are not induced by a TTX sensitive current.
February 1979
The American Journal of CARDIOLOGY
Volume 43
429