New concepts of antiarrhythmic drug actions.
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Animals↗
Biomedical subjects
R F Gilmour
Publications and source records attributed to R F Gilmour.
Slow inward current and cardiac arrhythmias.
The slow inward current contributes to the normal electrical and contractile activity of several cardiac and vascular tissues and also may mediate the electrical abnormalities responsible for certain cardiac arrhythmias. The slow inward current differs from the fast inward sodium current in that it is carried primarily by calcium rather than sodium, requires a more positive level of membrane potential to be activated, has slower activation and inactivation kinetics, is responsible for normal depolarization in sinus and atrioventricular (AV) nodal cells and is blocked by a rather specific group of agents that includes verapamil, diltiazem and nifedipine. Recent data suggest that slow-channel openings occur in bursts, separated by silent periods, and that less negative membrane potentials and beta-adrenergic stimulation increase the probability that the channels will open. Inactivation of the channels is associated with a lower probability of channel opening. Slow-channel blocking agents such as verapamil, diltiazem and nifedipine appear to bind to activated, rather than rested, slow channels. Therefore, their effects are more prominent at faster pacing rates and at less negative membrane potentials. Clinically occurring cardiac arrhythmias dependent on the slow inward current include primarily sinus and AV nodal reentry and reciprocating tachycardia in the Wolff-Parkinson-White syndrome when one of the pathways incorporates the AV node. Damaged atrial, ventricular and specialized tissue also can generate slow response-mediated reentry or forms of automaticity that may be clinically important under certain circumstances.
Animals↗
Assessment of urinary stream after repair of anterior hypospadias by meatoplasty and glanuloplasty.
Voiding function was studied after repair of anterior hypospadias in 44 boys using Duckett's technique of meatoplasty and glanuloplasty. Assessment of the urinary stream was done in 2 ways. At least 6 weeks postoperatively a uroflow measurement using a DISA rotating disk machine was done. Peak flow was compared to previously prepared normal values in a large group of normal boys. Then, a high speed picture of the stream was taken using electronic video photography at the time of peak flow. Of the boys 42 had normal flow rates and 40 had acceptable stream patterns. The only complication was meatal stenosis in 2 cases. There were no fistulas. Although the primary indication for correction of anterior hypospadias is cosmetic, it is essential that function not be sacrificed to achieve this end. This study indicates that voiding function is maintained after hypospadias repair with meatoplasty and glanuloplasty.
Adolescent↗
Positive inotropic effect of acetylcholine in canine cardiac Purkinje fibers.
The purpose of this study was to investigate possible mechanisms to explain the positive inotropic effects of acetylcholine in canine cardiac Purkinje fibers. Action potentials and tension were recorded from Purkinje fibers in vitro using microelectrodes and a force transducer. Acetylcholine (10(-9) to 10(-4) M) produced a dose-dependent increase in tension that was blocked by atropine but not by propranolol, phentolamine, hexamethonium, or verapamil. At 10(-5) and 10(-4) M, acetylcholine increased action potential duration at 50% of repolarization (APD50) but did not affect resting membrane potential, action potential amplitude, Vmax, or action potential duration at 90% of repolarization (APD90). Isoproterenol (10(-7) M) shortened APD50 and APD90 and increased developed tension. Subsequent addition of acetylcholine (10(-5) M) prolonged APD50 and APD90 and decreased tension. Increasing extracellular Ca2+ concentration [( Ca2+]o) from 2.0 to 3.0 mM increased tension and shortened APD50. Addition of acetylcholine (10(-5) M) increased tension further and prolonged APD50. In K+-depolarized fibers high concentrations of acetylcholine (10(-4) M) restored excitability, but lower concentrations (10(-6) M) suppressed slow responses induced by isoproterenol. Thus acetylcholine alone or with elevated [Ca2+]o increased APD50 and tension and facilitated the induction of slow responses, yet in the presence of isoproterenol acetylcholine increased APD50, decreased tension, and suppressed slow responses. These effects were mediated by muscarinic receptors and were independent of catecholamine release.
Acetylcholine↗
Rate-related suppression and facilitation of conduction in isolated canine cardiac Purkinje fibers.
Previous studies have shown that antegrade conduction through damaged His Purkinje tissue may be suppressed following rapid ventricular pacing (overdrive suppression of conduction). We studied this phenomenon using isolated Purkinje fibers placed in a three-chamber bath. Superfusates for the left, middle, and right segments of the fiber were altered to produce action potentials that resembled those of normal bundle branch, damaged His bundle, and normal His bundle, respectively. To produce anisotropic conduction, the left segment of the fiber was adjusted to be three to four times longer than the right segment. Pacing the right segment at intermediate rates produced maximal action potential amplitude in the middle segment and 1:1 right-to-left conduction, whereas pacing at faster or slower rates reduced action potential amplitude and produced block. Pacing the left segment at fast or slow rates also reduced action potential amplitude in the middle segment, but conduction was maintained (anisotropy). After rapid or slow left segment pacing, action potential amplitude in the middle segment remained low during subsequent right segment pacing at intermediate rates, and transient block occurred (overdrive or underdrive suppression of conduction). With time, action potential amplitude normalized and conduction resumed. In other more severely depressed preparations, conduction block occurred even at intermediate right segment pacing rates prior to left segment pacing. Under these conditions, pacing the left segment at intermediate rates increased action potential amplitude in the middle segment and temporarily permitted 1:1 conduction at intermediate right segment pacing rates (overdrive facilitation of conduction).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Basic electrophysiologic mechanisms for the development of arrhythmias. Clinical application.
The mechanisms responsible for the genesis of cardiac arrhythmias are frequently divided into categories of disorders of impulse formation, disorders of impulse propagation, or combinations of both. Classification of arrhythmias into these categories is based largely on the results of experimental studies, where the initiation and perpetuation of an arrhythmia can be studied in some detail in a relatively controlled environment.
Action Potentials↗
Evidence for prejunctional and postjunctional antagonism of the sympathetic neuroeffector junction by acetylcholine in canine cardiac Purkinje fibers.
This study determined whether acetylcholine inhibited changes in action potential duration and developed tension in canine Purkinje fibers produced by norepinephrine released during field stimulation more than it inhibited changes produced by superfusion with norepinephrine. Field stimulation increased action potential duration measured at 75% of repolarization by 9.6 ms and increased active tension by 35.5%. Acetylcholine (10(-6) M) almost completely inhibited changes in action potential duration and developed tension during field stimulation. Norepinephrine (10(-8) M to 5 X 10(-8) M) superfusion during normal pacing increased developed tension by 40.6%. Acetylcholine (10(-6) M) reduced this increase to 19.7%. Thus, acetylcholine inhibited the increase in tension during field stimulation by 90.7%, whereas it inhibited equivalent increases in tension produced by superfusion with norepinephrine by only 51.4% (p less than 0.01). These data suggest that acetylcholine antagonizes the effects of adrenergic stimulation by pre- and postjunctional inhibitory actions in canine cardiac Purkinje fibers.
Acetylcholine↗
Depressant effects of fast sodium channel blockade on the electrical activity of ischaemic canine ventricle: mediation by the sympathetic nervous system.
In this study we examined the possibility that local anaesthetic agents such as tetrodotoxin may exacerbate electrical changes during acute myocardial ischaemia by inhibiting fast sodium channels, both in cardiac cells and in sympathetic nerve terminals. Bipolar electrograms were recorded during serial 2 to 5 min occlusions of the left anterior descending coronary artery in open-chest, anaesthetised dogs. Tetrodotoxin (1 or 2 micrograms X kg-1 iv) given prior to occlusion did not affect activation times or electrograms in normal myocardium but exacerbated activation delay and loss of electrogram amplitude during ischaemia. Bilateral stellectomy reversed the effects of tetrodotoxin during ischaemia. Tetrodotoxin (1 microgram X kg-1 iv) reduced changes in heart rate and mean arterial blood pressure produced by stellate ganglia stimulation. Intracoronary infusion of tetrodotoxin (10(-5) mol X litre-1) during normal perfusion lengthened mean effective ventricular refractory periods and propranolol (0.5 mg X kg-1 iv) or bilateral stellectomy prevented this effect. Thus, tetrodotoxin appeared to increase ventricular refractoriness and exacerbate ischaemia-induced activation delay by inhibiting sympathetic nerve activity. Other agents with local anaesthetic properties may have similar effects.
Action Potentials↗
Purkinje-muscle coupling and endocardial response to hyperkalemia, hypoxia, and acidosis.
Previously we found that combined hyperkalemia, hypoxia, and acidosis depressed the electrical activity of canine epicardium more than that of endocardium or Purkinje fibers. In this study, we determined whether the resistance of endocardium to these components of ischemia was due to electrotonic interactions with Purkinje fibers. The effects of combined hyperkalemia, hypoxia, and acidosis were tested on endocardial cells that were electrically uncoupled from Purkinje cells ("uncoupled" endocardium), due to their location or to prior exposure to elevated [Ca2+]. During control, action potentials in uncoupled endocardium had shorter durations than endocardium coupled to Purkinje ("coupled" endocardium), but had similar amplitudes, upstroke velocities, and resting potentials. During combined hyperkalemia, hypoxia, and acidosis, action potentials in uncoupled endocardium were more depressed than in coupled endocardium and resembled those in depressed epicardium. In addition, the combination of these components of ischemia produced electrical uncoupling at the Purkinje-muscle junction, although each component alone did not. Thus the resistance of endocardial cells to some components of ischemia appears to involve electrotonic interactions with Purkinje cells, which may be prevented by ischemia-induced electrical uncoupling.
Acidosis↗
Overdrive suppression of conduction in the canine His-Purkinje system after occlusion of the anterior septal artery.
The purpose of these experiments was to determine whether overdrive suppression of conduction (OSC), i.e., transient worsening of conduction or development of atrioventricular block after cessation of rapid pacing, could be produced in the canine His-Purkinje system damaged by ligation of the anterior septal coronary artery and to investigate the responsible mechanism. We found that OSC occurred in vivo after rapid ventricular and His bundle pacing but not after atrial pacing, and that it occurred in vitro after rapid pacing from the left bundle branch but not after pacing from the proximal His bundle. OSC was related to the duration and cycle length of pacing. Lidocaine increased while verapamil reduced the duration of OSC in vivo. The mechanism responsible for the unidirectionality of OSC is not clear but is probably related to the geometry of the atrioventricular junction and the anterograde versus the retrograde activation sequence. Changes in regional myocardial blood flow, autonomic tone, hemodynamic variables, or ventricular function do not appear to be required to produce OSC, based on the demonstration of the phenomenon in vitro. The data suggest a time- and rate-dependent change in factors affecting conduction such as excitability or cell-to-cell coupling, possibly due to accumulation of intracellular cations such as calcium.
Animals↗
The effects of lidocaine and quinidine on impulse propagation across the canine Purkinje-muscle junction during combined hyperkalemia, hypoxia, and acidosis.
During ischemia, lidocaine or quinidine may prevent arrhythmias by blocking conduction without suppressing abnormal automaticity. The purpose of this study was to determine whether lidocaine or quinidine (5 micrograms/ml) produced Purkinje fiber-papillary muscle block during superfusion in vitro with an altered Tyrode's solution containing some components of ischemia: 6 mM potassium, PO2 less than 40, pH = 6.8. Unbranched canine Purkinje fibers connected to papillary muscle at one end were threaded through a three-chamber bath with Purkinje fiber-papillary muscle in the left chamber and Purkinje fiber alone in the middle and right chambers. Action potentials were recorded using microelectrodes from Purkinje fiber, papillary muscle, and cells at the Purkinje fiber-papillary muscle junction. Purkinje fiber or papillary muscle was stimulated at 1.5-4 Hz. Perfusion of the left chamber with altered Tyrode's solution decreased resting membrane potential, action potential amplitude, and the maximum rate of rise of phase 0 of the action potential of Purkinje fiber, papillary muscle, and junctional cells, and prolonged activation times of junctional cells and papillary muscle; but action potentials propagated from Purkinje fiber to papillary muscle, and from papillary muscle to Purkinje fiber. Lidocaine or quinidine plus altered Tyrode's solution further decreased action potential amplitude and the maximum rate of rise of phase 0 of the action potential of Purkinje fiber, papillary muscle, and junctional cells, and prolonged activation of junctional cells and papillary muscle, inducing bidirectional block only at the Purkinje fiber-papillary muscle junction. Lidocaine or quinidine plus normal Tyrode's solution and each component of altered Tyrode's solution alone did not produce block. Perfusion of the right chamber with 0.25 mM barium induced Purkinje fiber automaticity that: propagated to papillary muscle during perfusion of the left chamber with normal Tyrode's or altered Tyrode's solution; blocked at the Purkinje fiber-papillary muscle junction during perfusion of the left chamber with altered Tyrode's solution plus lidocaine; and was not suppressed during perfusion of the right chamber with lidocaine. Thus, lidocaine or quinidine may produce bidirectional block at Purkinje fiber-papillary muscle junction and interrupt a potential limb of a reentrant circuit without suppressing automatic arrhythmogenic foci.
Acidosis↗
Cellular electrophysiologic abnormalities of diseased human ventricular myocardium.
Using standard microelectrode techniques, the cellular electrophysiologic features of ventricular myocardium resected from 8 patients with refractory arrhythmias were studied in vitro. Action potentials from damaged myocardium compared with normal myocardium had reduced resting membrane potential, amplitude, and maximal upstroke velocity. Tetrodotoxin, but not verapamil, suppressed 3 action potentials with resting potentials of -60 to -64 mV and Vmax less than 70 V/s. Verapamil, but not tetrodotoxin, suppressed 4 action potentials with resting potentials of -44 to -57 mV and Vmax less than 20 V/s. Unidirectional block, Wenckebach block, and summation occurred in damaged zones. Exit block from and frequency-dependent entrance block into an ectopic focus were noted. Subthreshold responses in the focal area induced by action potentials in the surrounding myocardium and by subthreshold current pulses injected through the recording microelectrode altered the spontaneous discharge rate of the focus, as previously described for modulated parasystole. Pulses early in the spontaneous cycle delayed the next expected discharge, and later pulses accelerated the subsequent discharge. Pulses injected at the singular point completely suppressed automaticity (annihilation). Tetrodotoxin and verapamil suppressed automaticity in some fibers. Single action potentials induced in quiescent fibers triggered and terminated sustained rhythmic activity. These data suggest that depressed fast responses, slow responses, and subthreshold potentials can generate and modulate ectopic activity in damaged human ventricle and that fast- and slow-channel blocking agents and single premature stimuli can terminate such activity.
Action Potentials↗
Influence of the autonomic nervous system on the genesis of cardiac arrhythmias.
The purpose of this report is to present a brief overview of the concepts concerned with the potential effects of the autonomic nervous system on the genesis of cardiac arrhythmias. First, we present data indicating the functional importance of presynaptic and postsynaptic vagal modulation of adrenergic neurotransmission on electrical activity in sinus and A-V nodes, and contractile activity of canine cardiac Purkinje fibers. Second, we indicate the possible intraventricular adrenergic and vagal pathways to the ventricles, suggesting that sympathetic fibers travel in the epicardium while vagal fibers appear to cross the A-V groove in the epicardium but then take an intramural route for part of their course. Finally, we demonstrate that a lesion such as a myocardial infarction can interrupt neural fibers traveling through the infarction to affect noninfarcted myocardium distal to the infarction. These factors may play a role in the genesis of some cardiac arrhythmias.
Adrenergic Fibers↗
Cellular basis for cardiac arrhythmias.
The authors summarize current concepts of the cellular electrophysiologic basis for cardiac arrhythmias. The cellular mechanisms for abnormal formation and propagation of impulses and selected interactions between the two are reviewed. The clinical significance of these phenomena is also discussed.
Action Potentials↗
Calcium antagonists and their potential role in the prevention of sudden coronary death.
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Action Potentials↗
Electrophysiological response of vascularized hamster cardiac transplants to ischemia.
To study transmembrane electrophysiological properties of blood-perfused mammalian heart cells during normal perfusion and during acute ischemia, 1- to 2-mm cubes of neonatal hamster atrial and ventricular myocardium were transplanted to the adult hamster cheek pouch and studied with microelectrodes 4--7 days later, when vascularization and spontaneous contractions occurred. Action potentials recorded from the transplants were similar to those recorded from neonatal and adult hamster myocardium studied in vitro. Interrupting blood flow to spontaneously beating transplants reduced diastolic depolarization and suppressed automaticity. After automaticity ceased, the transplants were paced with a bipolar electrode or intracellular microelectrode. Action potential amplitude, resting potential, and dV/dtmax decreased during ischemia. Action potential duration and the intracellular current threshold for excitation increased initially, subsequently decreased to values less than control, and increased again prior to the onset of inexcitability. Conduction delay and block occurred during the late stages of ischemia. Depressed action potentials recorded during ischemia were suppressed by tetrodotoxin (10(-5) M) but not by verapamil (2 x 10(-6) M). These data indicate that: (1) the electrophysiological properties of cheek pouch cardiac transplants are normal, (2) ischemia suppresses transplant automaticity, (3) cellular excitability increases during the early stages of ischemia and decreases at a time when conduction delay and block occur, and (4) action potentials generated during the later stages of ischemia appear to be depressed fast responses, rather than slow responses.
Animals↗
Management of arrhythmias with "calcium antagonists".
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Arrhythmias, Cardiac↗
Effect of ethanol on electrogram changes and regional myocardial blood flow during acute myocardial ischaemia.
Acute occlusion of the left anterior descending coronary artery in dogs produced delayed conduction and diminished amplitude of bipolar electrograms recorded from ischaemic zones. Intravenous infusion of ethanol (1.2 g . kg-1), before coronary artery occlusion, delayed conduction and reduced the amplitude of electrograms recorded in normal myocardium, but attenuated ischaemia-induced electrogram changes produced by the subsequent occlusion. Ethanol (0.6 g . kg-1 iv) did not significantly alter activation of electrograms recorded from normal myocardium, but reduced ischaemia-induced electrogram changes and decreased the incidence of ventricular fibrillation elicited by rapid ventricular pacing from five of eight to one of eight dogs. Infusion of 10 or 30% (V/V) ethanol directly into a non-occluded coronary artery significantly increased conduction time and reduced electrogram amplitude recorded in the epicardium perfused by that coronary artery. These effects were more pronounced when ethanol was infused into an occluded coronary artery distal to the site of occlusion. Ethanol did not alter regional myocardial blood flow determined by labelled microspheres during ischaemia. Thus, despite a direct depressant effect on extracellular electrical activity recorded from normal and ischaemic myocardium, ethanol reduced the severity of ischaemia-induced electrogram alterations and decreased the incidence of ventricular fibrillation when given intravenously prior to coronary artery occlusion.
Acute Disease↗