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Biomedical subjects

M N Levy

Publications and source records attributed to M N Levy.

At least 55 records · Page 3Linked to original sources
PubMed1989

Muscarinic autoreceptors do not modulate kinetics of acetylcholine release in hearts.

We determined the time course of the cellular mechanism that mediates the attenuation of the chronotropic response in anesthetized dogs to decreases in the time interval (interpulse interval) between pulses of vagal stimuli. We injected propranolol, cut the cervical vagi, and repetitively stimulated the cardiac segment of the right vagus nerve with one brief burst of electrical pulses during each cardiac cycle. We recorded the initial and steady-state changes in cardiac cycle length that were induced by the phasic vagal stimulation. The decrease in the interpulse interval decreased the initial and steady-state responses. The time delay between the release of acetylcholine (ACh) from the vagal nerve endings in the heart and inhibition of the release of additional ACh was less than 4 ms. Published delays between the time of ACh release and the time of the resulting change in membrane potential, in other biological systems, are 30-12,000 ms. We conclude that the time delay was too brief for muscarinic autoreceptors to have mediated the attenuation of ACh release from postganglionic vagal nerve endings in the heart in response to decreases in interpulse interval.

Acetylcholine↗
PubMed1989

Effects of vagus nerve on heart rate and ventricular contractility in chicken.

We determined the effects of vagus nerve stimulation on cardiac cycle length and on ventricular contraction and relaxation in 18 chickens anesthetized with pentobarbital. Right vagus stimulation at a constant frequency of 35 Hz prolonged cycle length by 190%, whereas left vagus stimulation at the same frequency increased cycle length by 136%. When one burst of stimuli was delivered to the right vagus nerve each cardiac cycle, but the timing of the stimuli was changed within the cardiac cycle, the response of the avian pacemaker cells varied substantially with the timing of the stimuli. Right and left vagus stimulation at a constant frequency of 20 Hz depressed ventricular contraction by 62 +/- 6 and 52 +/- 6%, respectively, and depressed ventricular relaxation by 56 +/- 7 and 53 +/- 7%, respectively. These results indicate that in the chicken the chronotropic effects of right vagus stimulation are greater than those of left vagus stimulation, whereas right and left vagus stimulation are approximately equipotent on ventricular contraction and relaxation.

Animals↗
PubMed1989

Neuropeptide Y as a putative modulator of the vagal effects on heart rate.

Neuropeptide Y is stored in sympathetic nerve terminals throughout the heart and has direct and indirect effects on cardiac function. Although neuropeptide Y has been shown to be released upon intense (16-30 Hz) cardiac sympathetic stimulation, we sought to determine whether effective quantities of neuropeptide Y were released from cardiac sympathetic neurons under more natural conditions. We recorded arterial pressure and cardiac cycle length in 29 anesthetized dogs. We assessed neuropeptide Y release by measuring the attenuation of vagally induced increases in cardiac cycle length (10 seconds every 2 minutes) after trains of sympathetic stimulation. We examined the effect of constant-frequency sympathetic stimulation (frequencies of 2, 5, 10, and 15 Hz, applied for train durations of 1, 3, and 5 minutes) on vagally induced chronotropic responses. We also determined the effect of varying the pattern of sympathetic stimulation. Both the magnitude and duration of the inhibition of the vagal effects on cardiac cycle length were augmented significantly by increases in the frequency or duration of sympathetic stimulation. In contrast, the inhibition of the vagally induced chronotropic responses was not significantly affected by changes in the pattern of sympathetic stimulation. We also characterized the role of adrenergic receptors. Phentolamine significantly increased the sympathetically mediated inhibition of the vagal effects on cardiac cycle length, but propranolol had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Mathematical model of the changes in heart rate elicited by vagal stimulation.

We developed a mathematical model of the underlying cellular mechanisms responsible for the changes in sinus cycle length (SCL) elicited by vagal stimulation in intact animals. The model incorporated a stimulation-mediated depletion of the releasable pool of acetylcholine (ACh) in the nerve endings, the in vitro reaction kinetics of acetylcholinesterase, and the electrical activity of a pacemaker cell with six membrane ionic currents. SCL increased linearly with the frequency of simulated vagal stimulation, as it does in animal experiments, because the concentration of ACh in the neuroeffector junction [( ACh]) saturated as the frequency of stimulation was increased and because SCL increased geometrically in response to increases in [ACh]. The dependence of SCL on the timing of vagal stimulation in the cardiac cycle resulted, in part, from the dependence of [ACh] on SCL. Simulated vagal stimulation entrained the sinus node because the rate of activation and inactivation of ACh-activated K+ channels depended only weakly on membrane potential during diastolic depolarization. SCL increased geometrically with [ACh], because 1) during diastolic depolarization, the amplitude of the ACh-activated K+ current was approximately equal to the amplitude of the sum of the other ionic currents, 2) [ACh] was low enough to saturate neither acetylcholinesterase nor the cellular system that activates the ACh-activated K+ channels, 3) the pacemaker cell membrane behaved electrotonically like a capacitor, and 4) the sum of all the ionic currents increased linearly with the amplitude of the ACh-activated K+ current.

Acetylcholine↗
PubMed1989

Inhibition of cardiac vagal effects by neurally released and exogenous neuropeptide Y.

Neuropeptide Y (NPY) attenuates vagal effects on cardiac cycle length, presumably by inhibiting the release of acetylcholine from vagal nerve endings. We sought to determine if NPY inhibited the vagal effects on atrioventricular (AV) interval and atrial contraction in a manner similar to its inhibition of the vagal effects on cycle length. In 19 anesthetized dogs we measured the vagal effects on cycle length, AV interval, and atrial contraction before and after 3-minute trains of sympathetic stimulation or before and after exogenous NPY (20 micrograms/kg i.v.). Three minutes after 10-Hz sympathetic stimulation, the vagal effects on cycle length and AV interval were attenuated by 52 +/- 9% and 63 +/- 8%, respectively. Phentolamine significantly augmented this attenuation, but propranolol had no appreciable effect. In the control group of animals or in the group that received phentolamine, the vagal effects on atrial contraction measured before and after sympathetic stimulation were not significantly different. In these two groups, however, the basal atrial contraction was reduced substantially after the cessation of sympathetic stimulation. Propranolol prevented this reduction in atrial contraction. After propranolol, the vagal effects on atrial contraction 3 minutes after sympathetic stimulation were attenuated by 31 +/- 6%. Exogenous NPY had no direct effect on cycle length, AV interval, or atrial contraction, but exogenous NPY did persistently inhibit the vagal effects on each of these cardiac processes. Three minutes after NPY was given, the vagal effects on cycle length, AV interval, and atrial contraction were inhibited by 62 +/- 7%, 69 +/- 5%, and 68 +/- 5%, respectively. We conclude that NPY attenuates the vagal effects on the atrial myocardium and on the sinus and AV nodes. In the absence of beta-blockade, the inhibitory effect of neurally released NPY on the vagally induced decreases in atrial contraction may be masked by the reduction in the atrial contraction that occurs after sympathetic stimulation.

Animals↗
PubMed1989

Role of calcium in arrhythmogenesis.

Cardiac arrhythmias are generated as the result of disorders of automaticity or impulse conduction. Regardless of the mechanism, however, calcium is likely to be involved. The rate of Ca2+ flux across the membrane of automatic cells alters their firing rate. Myocardial cells that do not ordinarily initiate action potentials can do so when they are partially depolarized. Low extracellular Ca2+ concentrations or Ca2+ channel-blocking drugs can reduce or abolish such ectopic firing. Early afterdepolarizations are also induced in cardiac cells by partial depolarization, whereas delayed afterdepolarizations are induced by Ca2+ overloading. Early afterdepolarizations and delayed afterdepolarizations can both be suppressed by low external Ca2+ concentrations or by Ca2+ channel blockers. With respect to arrhythmias ascribable to disorders of conduction, Ca2+ channel blockers can aggravate conduction disturbances in the sinoatrial node or atrioventricular junction. Furthermore, these drugs can abolish those reentrant arrhythmias in which a cardiac impulse rotates around a loop in which nodal tissue is an integral element. Ca2+ channel blockers can also reduce the susceptibility for ventricular fibrillation to supervene in ischemic hearts, especially when the sympathetic nervous system is overactive.

Animals↗
PubMed1987

Rate of acetylcholine hydrolysis affects the phase dependency of cardiac responses to vagal stimulation.

The influence of the rate of acetylcholine hydrolysis on the magnitude and phase dependency of the cardiac chronotropic response to vagal stimulation was studied in anaesthetised dogs. In one group of animals the chronotropic response to tonic vagal stimulation varied directly with the dose of physostigmine. In a second group of animals one brief stimulus burst was delivered to the right vagus nerve during each cardiac cycle, and the timing (phase) of the stimulus was varied within the cycle. Before physostigmine was given the phase of the stimulus had a substantial influence on the chronotropic response. When each stimulus burst contained 6 pulses the response was changed from its minimum to its maximum value (mean (SEM) change 0.338(0.081) s) when the phase was shifted by a mean value of 0.091(0.031) s. After physostigmine (0.3 mg X kg-1) was given the change in response produced by a phase shift was much less pronounced. A mean shift in phase of 0.593(0.052) s was required to change the chronotropic response from its minimum to its maximum value, and the mean difference between the minimum and maximum response was only 0.140(0.032) s. Hence the rate of acetylcholine hydrolysis in the cardiac tissues is an important determinant of the phase dependency of the chronotropic response to repetitive vagal stimulation-that is, the slower the rate of hydrolysis the less the change in the chronotropic response elicited by a given change in stimulus timing.

Acetylcholine↗
PubMed1987

Increased heart rate accelerates norepinephrine washout from normal myocardium.

We determined whether a change in heart rate affected the decay of the ventricular inotropic response to sympathetic stimulation in an experimental group and in a control group of anesthetized dogs. We induced complete heart block in each animal and paced the ventricles at rates of 90, 120, and 150 min-1 during two observation periods. In the experimental group, desipramine hydrochloride was given during the second period to block the neuronal uptake mechanism. The control animals did not receive desipramine during either period. The time required for the ventricular inotropic response to decay by 50% after cessation of a 2-min train of sympathetic stimulation was used as an index of the rate of norepinephrine washout from the myocardial interstitium. As we increased the pacing rate over the range of 90-150 min-1 in the experimental group, the mean decay half times (+/- SE) decreased by 36 +/- 4% (P less than 0.001) before desipramine and by 26 +/- 6% (P less than 0.001) in the presence of desipramine. These decrements in the decay half times were not significantly different from each other. The mean decay half times decreased by 36 +/- 4% (P less than 0.001) in the control dogs; the effects did not change appreciably from the first to the second observation period. We conclude that an increase in pacing frequency facilitates the washout of norepinephrine from the ventricular myocardium; this facilitation is equally pronounced regardless of whether the neuronal uptake mechanism is intact or suppressed.

Animals↗
PubMed1986

Concealed ventricular premature complexes in a population sample.

One hundred fifty patients were analyzed with a random sample of patients whose Holter recordings indicated ventricular premature complexes (VPCs). Thirty-five patients (23%) had more than 30 VPCs/hour. Of these 35 patients, 19 had concealed VPCs. This represents 54% of the patients with more than 30 VPCs/hour and 13% of the total sample of 150 patients with VPCs. The most common type of concealed VPCs was the classic concealed bigeminy (S = 2n - 1), which was found in 10 of 19 patients (52%) whose electrocardiograms and patterns were characteristic of concealed VPCs. This was followed by the "even variant" 2n in 5 patients (26%), concealed trigeminy (S = 3n - 1) in 1 (5%), the 3n - 2 variant in 1 (5%) and the "interpolated variant" of 1 + (2n - 1) in 1 (5%). One patient showed a conversion from 2n - 1 to 2n.

Adult↗
PubMed1985

Responses of the atrial myocardium to cardiac sympathetic nerve stimulation.

The cardiac responses to sympathetic nerve stimulation were measured in open-chest, anesthetized dogs before and after infusions of cocaine, which were given to inhibit the neuronal uptake of norepinephrine. Cocaine did not augment the inotropic or chronotropic responses, but it did retard their decay after cessation of sympathetic stimulation. Before cocaine, the half-times for decay of the chronotropic, atrial inotropic, and ventricular inotropic responses were 28.4 +/- 2.2, 29.8 +/- 2.7, and 22.1 +/- 1.9 (+/- SE) s, respectively. After cocaine, however, the half-times were significantly greater (147 +/- 12.0, 51.4 +/- 3.9, and 32.9 +/- 2.5 s, respectively). The cocaine-induced prolongation of the decay time in a given cardiac tissue is a measure of the relative efficacy of neuronal uptake as a mechanism for dissipating the neurally released norepinephrine. Our data indicate, therefore, that among the various cardiac tissues that we studied, the neuronal uptake mechanism is least effective in the ventricular myocardium, somewhat more effective in the atrial myocardium, and most effective in the sinoatrial nodal region.

Animals↗
PubMed1985

Sustained increases in heart rate induced by timed repetition of vagal stimulation in dogs.

We determined the influence of the "free-running cycle length" (tau FR) on chronotropic responses to one burst of right vagal stimuli per cardiac cycle in anesthetized dogs (tau FR, cycle length that prevailed in absence of right vagal stimulation). We varied tau FR by the following methods: 1) tonic left vagal stimulation in pentobarbital-anesthetized animals; 2) tonic left vagal stimulation plus sinus node cooling in pentobarbital-anesthetized animals; and 3) anesthesia with fentanyl, droperidol, and pentobarbital. When tau FR was less than a critical value [1,019 +/- 60 (SE) ms], right vagal stimulus bursts always had the expected negative chronotropic effect. However, when the tau FR was increased beyond critical value, right vagal stimulus bursts delivered within a specific portion of cardiac cycle actually had a positive chronotropic effect; i.e., cycle lengths diminished to values below tau FR. As tau FR was progressively increased beyond critical value, positive chronotropic response became greater and could be evoked by stimulus bursts delivered within a greater fraction of cardiac cycle. The right vagal stimuli that elicited the maximum positive chronotropic effect were those that were given approximately 235 ms prior to beginning of next atrial depolarization. This critical time probably occurs near the end of the period of phase 4 depolarization of sinus node automatic cells.

Acetylcholine↗
PubMed1985

Heart rate modulates the disposition of neurally released norepinephrine in cardiac tissues.

We determined the effect of heart rate on the disposition of neurally released norepinephrine from the cardiac tissues in open-chest, anesthetized dogs with complete atrioventricular block. After injecting desipramine to block the neuronal uptake of norepinephrine, we stimulated the cardiac sympathetic nerves supramaximally for about 3 minutes at a mean frequency of 2.7 Hz. In one series of experiments, we allowed coronary sinus blood flow to change spontaneously in response to cardiac pacing and sympathetic stimulation. The mean coronary sinus blood flows just before cessation of sympathetic stimulation were 67.4 +/- 4.2 (SE) and 37.4 +/- 2.7 ml/min during pacing at a high (150/min) and a low (60/min) frequency, respectively. The mean norepinephrine overflow into the coronary sinus blood during steady state sympathetic stimulation was 45.0 +/- 14.2% greater during high frequency pacing than during low frequency pacing. After cessation of neural stimulation, the norepinephrine overflow decayed more rapidly during high frequency pacing than during low frequency pacing. This difference in decay rates was mainly ascribable to the difference in coronary blood flows. In a second series of experiments, we adjusted the coronary sinus blood flow during sympathetic stimulation so that the flows were not significantly different during pacing at the two frequencies. During the initial 30-second period, after cessation of sympathetic stimulation, the mean decrements of norepinephrine overflow were 95.9 +/- 21.4 and 59.2 +/- 17.3 ng/min at the high- and low-pacing frequencies, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The effects of neuronal uptake blockade on the cardiac responses to sympathetic nerve stimulation and norepinephrine infusion in anesthetized dogs.

In anesthetized dogs, cocaine ( COC ) was administered intravenously in order to block the neuronal uptake of norepinephrine (NE) by the heart. COC had relatively little effect on the magnitudes of the inotropic and chronotropic responses to sympathetic stimulation, but it did prolong the decay times, especially those of the chronotropic responses. The marked prolongation of the decay times of the chronotropic responses indicates that neuronal uptake must be the main mechanism for dissipating the adrenergic transmitter in the sinus node. However, this mechanism appears to be less important in the ventricular myocardium. At all dosage levels, COC increased the overflow of NE into the coronary sinus blood during cardiac sympathetic stimulation. The extraction of exogenously infused norepinephrine by heart tissue varied inversely with the dose of COC , indicating that the extent of neuronal uptake blockade increased with the dose. Nevertheless, NE overflow into the coronary sinus blood after a relatively large dose (5.7 mg/kg) of COC was less than that observed after a much smaller dose (0.5 mg/kg), suggesting that relatively large doses of COC also tend to inhibit the neuronal release of NE. These results indicate that the effects of COC on the cardiac responses to sympathetic stimulation depend on the balance between its influences on the release and dissipation of neurotransmitter in the neuroeffector gap.

Animals↗
PubMed1984

Effects of ouabain and vagal stimulation on heart rate in the dog.

When the vagus nerves are stimulated with one burst of pulses per minute, but each burst is placed at a different time in the cardiac cycle, a "vagal effect curve" can be derived which displays the changes in cardiac cycle length (CCL) as a function of the elapsed time from the stimulus. This curve consists of a primary and a secondary phase of increased CCL. We performed experiments on open-chest anaesthetised dogs to test the hypothesis that the secondary phase of increased CCL is caused by an increase in the activity of the electrogenic Na+/K+ pump. In animals with a sinoatrial nodal rhythm (SANR), the mean peak values of the primary and secondary phases of increased CCL were 0.48 +/- 0.03 and 0.06 +/- 001 s, respectively, above the prestimulation level (0.52 +/- 0.01 s). Ouabain (40 micrograms X kg-1 iv) did not significantly alter this bimodal response. In animals with an atrioventricular junctional rhythm (AVJR), the peaks of the primary and secondary increases in CCL were 0.55 +/- 0.03 and 1.04 +/- 0.17 s, respectively, above the prestimulation level (0.72 +/- 0.02 s). In animals with AVJR, ouabain markedly attenuated the peak secondary increase in CCL to 19% of the corresponding control value. This attenuation supports the hypothesis that the prominent secondary increase in CCL evoked by a brief vagal stimulus during AVJR is ascribable to an increased activity of the electrogenic Na+/K+ pump.

Animals↗