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Biomedical subjects

M N Levy

Publications and source records attributed to M N Levy.

At least 19 recordsLinked to original sources
PubMed1997

Effect of phasic vagal stimulation and atrial pacing site on atrioventricular conduction time.

We tested the hypothesis that the effect of phasic vagal stimulation on atrioventricular (AV) conduction time is affected by the site of atrial pacing in anesthetized dogs. We paced the right atrium at a constant cycle length from the interatrial septum (IAS), superior coronary sinus (SCS), or inferior coronary sinus (ICS) regions, and we evaluated the time-dependent effects of vagal stimulation on AV conduction at each pacing site. When we stimulated the vagi at stimulus (St)-A phases greater than 136 +/- 40 ms and less than the phase that blocked AV conduction (182 +/- 70 ms), IAS pacing prolonged A-V intervals by 8.6 +/- 8.2 ms more than ICS pacing. A change in pacing site affected the A-V intervals by up to 30 ms when we stimulated the vagus at those times that caused the A-V intervals to prolong maximally. Furthermore, the effect of atrial pacing site on A-V intervals was modulated by AV nodal recovery times during the second or third cycles after the vagal stimulus.

Animals↗
PubMed1997

Effects of ionic channel antagonists barium, cesium, and UL-FS-49 on vagal slowing of atrial rate in dogs.

In response to a brief vagal stimulus, the atrial rate initially slows, then transiently accelerates, and slows a second time. We determined the effects of three antagonists to two ionic channels on this characteristic triphasic pacemaker response. Brief bursts of vagal stimulation were delivered to anesthetized dogs, and atrial cycle lengths were recorded. Either barium, cesium, or UL-FS-49 was administered. Barium, which primarily blocks the acetylcholine-sensitive potassium current (IK,ACh), attenuated the initial vagally induced bradycardia by > 50% without affecting the subsequent acceleration or the secondary slowing. Cesium and UL-FS-49 [both of which primarily block the pacemaker current (If)] did not affect the initial vagal slowing of atrial rate but abolished the acceleratory portion of the response. The secondary slowing was abolished by cesium but not by UL-FS-49. We conclude that the initial rapid atrial response to acetylcholine is mediated mainly by the IK,ACh, with little contribution from the If. The subsequent acceleration is mediated by activation of the If.

Acetylcholine↗
PubMed1997

Neural control of cardiac function.

The principal functions of the heart are regulated by the sympathetic and parasympathetic divisions of the autonomic nervous system. In general, the sympathetic nerves to the heart are facilitatory, whereas the parasympathetic (vagus) nerves are inhibitory. The kinetics of the two autonomic divisions differ substantially. The vagal effects develop very rapidly, often within one heartbeat, and they decay quickly as well. Hence, the vagus nerves can exert beat-by-beat control of cardiac function. Conversely, the onset and decay of the sympathetic effects are much more gradual; only small changes are effected within the time of one cardiac cycle. When both autonomic systems act concomitantly, the effects are not additive algebraically, but complex interactions prevail. Such interactions may be mediated either pre-junctionally or post-junctionally with respect to the neuro-effector junction.

Animals↗
PubMed1995

Effects of repetitive vagal stimulation on heart rate and on cardiac vasoactive intestinal polypeptide efflux.

In dogs anesthetized with alpha-chloralose, we assessed the "vagally induced tachycardia" elicited by successive 2-min periods of intense vagal stimulation (0.5 ms, 10 mA, 20 Hz) after we had blocked the animals' muscarinic and beta-adrenergic receptors with atropine and propranolol, respectively. We found that the tachycardia produced by the successive vagal stimulations progressively decreased to < 20% of the initial tachycardia response within 84 min. We also observed that the chronotropic response to vasoactive intestinal polypeptide (VIP) injected into the sinus node artery after the vagal stimulation regimen did not differ significantly from the response to the same dose of VIP injected prior to vagal stimulation. This finding indicates that the postjunctional responsiveness of the cardiac pacemaker cells had not diminished over the course of the vagal stimulation regimen. In isolated, perfused right atrial preparations, we observed a close correlation between the efflux of VIP from the atrial tissues and the chronotropic responses to vagal stimulation. Our results support the hypotheses that 1) VIP is a mediator of vagally induced tachycardia, 2) the reduction in VIP efflux is associated with a diminished vagally induced tachycardia, and 3) the reduced efflux of VIP probably reflects a diminution in neuronal release, perhaps by depletion of this peptide from the vagus nerve endings consequent to the prolonged neural stimulation.

Animals↗
PubMed1995

Vasoactive intestinal polypeptide antagonists attenuate vagally induced tachycardia in the anesthetized dog.

We used three vasoactive intestinal polypeptide (VIP) antagonists, VIP-(10-28), [p-Cl-D-Phe6,Leu17]VIP, and NT-VIP, to evaluate the role of VIP as a mediator of vagally induced tachycardia in chloralose-anesthetized dogs. After we administered muscarinic and beta-adrenergic receptor antagonists, we evoked vagally induced tachycardia either directly, by stimulating the vagus nerves for 2 min, or reflexly, by injecting phenylephrine to increase blood pressure. Furthermore, each of the antagonists attenuated the tachycardias induced by vagal stimulation by approximately 50% and the reflexly induced tachycardias by approximately 70%. Each VIP antagonist attenuated the chronotropic responses that we evoked by injecting VIP (5.2 ng/kg) into the sinus node artery. We tested the specificity of these VIP antagonists by determining whether they attenuated the increases in heart rate evoked by two other neuropeptides [peptide histidine isoleucine (PHI) and glucagon]. VIP-(10-28) attenuated the response to PHI, but not to glucagon. The other two VIP antagonists did not alter the chronotropic responses to PHI or glucagon. Our results support the hypothesis that neurally released VIP is the principal mediator of vagally induced tachycardia in the dog.

Animals↗
PubMed1995

Effects of estrogen in vivo on coronary vascular resistance in perfused rabbit hearts.

Estrogen or its vehicle was given daily to three groups of ovariectomized rabbits for various lengths of time, after which coronary flow was measured in their isolated perfused hearts. In one group, intramuscular injections of estrogen (40 micrograms/kg) for 7 or 14 days increased coronary flow by 40-50% (P < 0.05). In rabbits given estrogen intramuscularly for 7 days, the coronary flow returned to the basal level within 7 days after the estrogen injections were discontinued. In a second group of animals, intravenous injections of estrogen (10 micrograms/kg) for 4 days increased the coronary flow by 45% (P < 0.01). In a third group, we administered the estrogen transdermally for 4 days, and we measured the plasma estrogen levels at the end of this period. The coronary flow in this group was increased by 52% (P < 0.001), and the plasma estrogen levels ranged from 39 to 800 pg/ml. In all groups of experiments, the increments in coronary flow evoked by estrogen were virtually abolished by NG-nitro-L-arginine, an inhibitor of nitric oxide synthase. We conclude that estrogen regulates coronary blood flow, in part by upregulating nitric oxide synthase in the coronary vasculature.

Administration, Cutaneous↗
PubMed1994

Effects of coronary artery occlusion and reperfusion on the idioventricular rate in anesthetized dogs.

OBJECTIVES: We evaluated the effects of alpha 1- and beta-adrenergic receptor blockade on the changes in idioventricular rate induced by occlusion and reperfusion of the left anterior descending coronary artery in anesthetized dogs. BACKGROUND: Because sinus rate usually exceeds idioventricular rate, the experimental induction of complete atrioventricular (AV) block may improve the definition of the effects of coronary occlusion and reperfusion on idioventricular pacemaker mechanisms. METHODS: We injected formaldehyde into the AV node to induce complete AV block in 35 chloralose-anesthetized dogs. Animals were assigned to untreated (n = 22), prazosin-treated (n = 6) and propranolol-treated (n = 7) groups. We paced the hearts at 120 beats/min during a 20- to 60-min period of complete coronary occlusion, but we did not pace the heart during reperfusion. RESULTS: In the untreated group, the idioventricular rate did not change significantly during coronary artery occlusions of 20 or 40 min, but it did increase significantly during the last 20 min of a 60-min occlusion. Prazosin and propranolol each attenuated but did not abolish this rate increase. The idioventricular rate increased markedly but transiently soon after reperfusion in all untreated animals. This tachycardia was virtually abolished by either prazosin or propranolol. CONCLUSIONS: The increase in idioventricular rate that develops during the last 20 min of a 60-min coronary occlusion is modulated but probably not mediated by adrenergic mechanisms. The pronounced ventricular tachycardia after reperfusion is virtually abolished by either alpha 1- or beta-adrenergic antagonists. Hence, this tachycardia requires the simultaneous activation of alpha 1- and beta-adrenergic mechanisms in dogs.

Analysis of Variance↗
PubMed1994

Antecedent sympathetic stimulation alters time course of chronotropic response to vagal stimulation in dogs.

We determined the influence of antecedent sympathetic stimulation on the chronotropic responses of the heart to 10-s strains of vagal stimulation in anesthetized dogs. We used the reciprocal of the slope (m-1) of the initial portion of the vagal response as an index of the time required for the response to reach steady state. In one group of 11 animals, we found that the onset of the response to the vagal stimulation was progressively blunted as we increased the frequency and duration of the antecedent sympathetic stimulation; that is, m-1 increased from 0 to 8.13 +/- 2.75 (SE) and from 0 to 8.22 +/- 2.26, respectively. In three other animals, an antecedent infusion of norepinephrine had a blunting effect that resembled that of antecedent sympathetic stimulation. In 11 other animals, m-1 significantly decreased as we prolonged the elapsed time from the end of sympathetic stimulation to the beginning of vagal stimulation. In six other animals, m-1 was not affected by antecedent atrial pacing at frequencies that were equivalent to those elicited by antecedent sympathetic stimulations. The blunting effect of antecedent sympathetic stimulation was abolished by propranolol administration (1 mg/kg), but it was not affected appreciably by phentolamine administration (2 mg/kg). We conclude that the major blunting effect of antecedent sympathetic stimulation is mediated postjunctionally (i.e., at the level of the automatic cells in the heart.

Animals↗
PubMed1994

Chronic post thoracotomy pain.

Chronic post-thoracotomy pain (CPP) is a vexing clinical problem whose management has received scant attention. In order to identify the risk factors associated with CPP and determine the optimal treatment, the records of 238 consecutive patients who underwent thoracotomy were reviewed. CPP was defined as discomfort requiring the regular administration of analgesics that continued more than three months following surgery. CPP was present in 25 (11%) patients: 10/20 (50%) chest wall resections, 5/25 (20%) pleurectomies, 10/193 (5%) pulmonary resections. Among the 23 patients who required preoperative narcotics, 12 (52%) developed CPP. Improved pain control and decreased narcotic use was achieved via the administration of nonsteroidal anti-inflammatory medication and tricyclic anti-depressants. In addition, 10/25 patients required 11 pain procedures: trigger-point injection, intercostal blocks, injections of epidural steroids, stellate ganglion block. Recurrent pain occurred in 20 patients following initial control. All were found to have tumor regrowth. We conclude that CPP occurs more commonly following chest-wall resection and pleurectomy, and that preoperative narcotic use is a predictor of CPP. Worsening pain following initial relief should prompt a vigorous search for recurrent cancer.

Adult↗
PubMed1993

Frequency dependence of vasoactive intestinal polypeptide release and vagally induced tachycardia in the canine heart.

We evaluated the frequency dependence of vasoactive intestinal polypeptide (VIP) release from the parasympathetic nerves to the canine heart. In intact animals in the presence of beta-adrenergic receptor blockade (propranolol, 0.5 mg/kg), the cervical vagosympathetic trunks were stimulated at various frequencies before and after the administration of atropine (0.1 mg/kg). The stimulations before atropine produced a classical bradycardia that progressed to cardiac arrest when the stimulation frequency was raised above 10 to 15 Hz. After atropine, vagal stimulation at various frequencies increased heart rate. The heart rate reached a maximum increase of 21 +/- 3 beats per min at a stimulation frequency of 20 Hz. In an isolated atrial preparation in which the VIP outflow was measured, the tachycardia elicited after atropine had a frequency dependence similar to that obtained in vivo. The peak increase of 23 +/- 3% above the basal rate (95 +/- 8 beats per min) occurred at a stimulation frequency of 20 Hz. The VIP outflow paralleled the tachycardia response (r = 0.95); the maximum outflow of VIP was 172 +/- 54 pg/(min . 100 g wet wt) and was evoked at a stimulation frequency of 20 Hz. This suggests that the vagally induced tachycardia is mediated, at least partly, by VIP.

Animals↗
PubMed1993

Assessment of beat-by-beat control of heart rate by the autonomic nervous system: molecular biology technique are necessary, but not sufficient.

Vagus nerve activity can change heart rate substantially within one cardiac cycle, and the chronotropic effects decay almost completely within one cardiac cycle after cessation of vagal activity. The ability of the vagus nerves to regulate heart rate beat by beat can be explained in large part by the speed at which the neural signal is transduced to a cardiac response and by the rapidity of the processes that restore the basal heart rate when vagal activity ceases. Currently, the question of whether the cardiac cells can transduce the sympathetic neural signals rapidly enough to implement beatwise regulation is controversial. Emphasis on the speed of the processes that initiate the responses may, however, be misplaced. Instead, the processes that terminate the responses to autonomic neural activity (especially those processes that remove the released neurotransmitters) are probably the main determinants of the ability of the vagal and sympathetic systems to affect beatwise control. The norepinephrine (NE) released from the sympathetic nerve endings is removed from the cardiac tissues much more slowly than is the acetylcholine that is released from the vagal terminals. As a consequence of the potential deleterious effects associated with the slow removal of NE, the cardiac neural control system has evolved such that the sympathetic nerves ordinarily release NE at a slow rate. Hence, changes in sympathetic neural activity can alter cardiac behavior only slightly from beat to beat. Hence, beatwise control of cardiac function would be negligible, regardless of how swiftly the sympathetic nerve impulse is transduced to a change in cardiac performance.

Acetylcholine↗
PubMed1993

Modulation by extracellular ATP of two distinct currents in rat myocytes.

The whole cell voltage-clamp technique was used to study the electrophysiological effects induced by ATP in isolated ventricular myocytes. ATP or 2-methylthio-ATP evoked a transient inward current (IATP) when the transmembrane potential (Vm) was held at -70 mV and increased the Ca2+ current (ICa) when Vm was depolarized to 0 mV. The time course of IATP was fitted by a single exponential equation with a brief time constant (165 ms), whereas the time course of enhancement of ICa by ATP was also fitted by a single exponential equation with a much longer time constant (14 s). IATP was much less pronounced when extracellular Mg2+ was absent, and it was insensitive to dihydropyridines. In contrast, the enhancement of ICa by ATP was not affected by removing extracellular Mg2+, but it was suppressed by Ca2+ channel blockers. Both IATP and ICa were decreased by extracellular Cd2+. Internally applied guanosine 5'-O-(2-thiodiphosphate), which prevents the activation of G proteins, abolished the ATP-enhanced rise in ICa but did not inhibit IATP. These data suggest that ATP elicits IATP and increases ICa through two different mechanisms. IATP appears to be generated via receptor-operated channels that are activated by ATP. The ATP-induced increase of ICa appears to be mediated by G proteins via pathways that are independent of adenosine 3',5'-cyclic monophosphate and phosphoinositide turnover.

Adenosine Triphosphate↗
PubMed1993

Effects of intense antecedent sympathetic stimulation on sympathetic neurotransmission in the heart.

We studied the effects of intense sympathetic stimulation on the chronotropic responses of the heart to subsequent test stimulations of the cardiac autonomic nerves in dogs anesthetized with alpha-chloralose. Such intense sympathetic stimulations (which we refer to as "release stimulations") are known to release neuropeptide Y as well as norepinephrine. The changes in cardiac cycle length evoked by vagal and sympathetic test stimulations were progressively more attenuated as we increased the frequency and duration of the antecedent sympathetic release stimulations. We found that 2.5 minutes after a maximal release stimulation (30 Hz for 5 minutes), the mean +/- SEM chronotropic responses to the vagal and sympathetic test stimulations were diminished to 36.5 +/- 1.6% and 54.7 +/- 1.3% respectively, of the prestimulation responses. The mean times for the chronotropic responses to the vagal and sympathetic test stimulations to recover to their control values were 52.0 +/- 1.3 and 63.2 +/- 2.9 minutes, respectively. This enduring effect suggests the action of a neuropeptide, such as neuropeptide Y. Phentolamine potentiated the inhibitory effects of the sympathetic release stimulations. The chronotropic responses to isoproterenol infusions were not affected appreciably by antecedent sympathetic release stimulation. We conclude, therefore, that the inhibitory effects of antecedent sympathetic release stimulation on cardiac sympathetic neurotransmission are mediated prejunctionally, probably via an inhibition of the neuronal release of norepinephrine by neuropeptide Y.

Acetylcholine↗
PubMed1993

Intense sympathetic stimulation releases neuropeptide Y but fails to evoke sustained coronary vasoconstriction in dogs.

We determined whether a 3-minute period of intense cardiac sympathetic stimulation, which is known to release neuropeptide Y (NPY), elicits a sustained poststimulatory coronary vasoconstriction in anesthetized dogs that had received propranolol. We also periodically measured the cardiac chronotropic responses to test vagal stimulations; these responses served as an index of the neuronal release of NPY. In a group of 11 animals, the coronary vascular resistance increased by 14 +/- 4% during the sympathetic stimulation. After cessation of stimulation, however, coronary vascular resistance returned rapidly to its control value. The cardiac responses to the test vagal stimuli were attenuated by approximately 40% after cessation of sympathetic stimulation, and this inhibitory effect persisted for approximately 60 minutes. In a second group of eight dogs, we determined whether the intense sympathetic stimulation potentiates the coronary vascular responses to exogenous norepinephrine (NE). Before sympathetic stimulation, standard intracoronary infusions of NE increased coronary vascular resistance by 14 +/- 2%. Intense antecedent sympathetic stimulation did not alter the coronary vascular responses to subsequent NE infusions. However, the chronotropic responses to test vagal stimuli were initially attenuated by approximately 30%, and this inhibitory effect persisted for approximately 1 hour. In a third group of four dogs, we found that exogenous NPY significantly potentiated the coronary vasoconstriction evoked by NE infusions. The coronary vascular responses to combined infusions of NE and NPY were consistently greater (by approximately 13%) than the sum of the responses to these substances when they were infused separately. We conclude that, even though sufficient NPY appears to be released from the sympathetic nerve endings to inhibit vagal neurotransmission, the quantity of NPY released into the coronary blood vessels under the conditions of our experiments appears to be insufficient either to elicit a sustained coronary vasoconstriction or to potentiate the vasoconstrictor effects of intracoronary NE infusions.

Animals↗
PubMed1992

Analysis of vagally induced sinus arrhythmias.

Vagal stimulation at precise times in successive cardiac cycles can elicit sinus arrhythmias. Two mechanisms have been identified that can, but do not necessarily, cause these vagally induced sinus arrhythmias. First, changes in cycle length elicited by a given concentration of acetylcholine (ACh) depend on the phase of the pacemaker cell action potential when the ACh binds to muscarinic receptors. Second, acetylcholinesterase degrades ACh rapidly enough for the mean concentration of ACh per cardiac cycle to vary from cycle to cycle. We used a mathematical model of the underlying cellular physiology, to examine whether these mechanisms are responsible for arrhythmogenesis. Computer simulation showed that both mechanisms contribute to the vagally induced sinus arrhythmias.

Arrhythmias, Cardiac↗
PubMed1992

Synergism between cAMP and ATP in signal transduction in cardiac myocytes.

ATP transiently increases the intracellular Ca2+ concentration in cardiac myocyte suspensions. Pretreatment with norepinephrine (NE) greatly potentiates the ATP response. We performed experiments on adult rat myocyte suspensions loaded with fura-2 to investigate the mechanism of NE potentiation. We found that forskolin (an activator of adenylate cyclase), 3-isobutyl-1-methylxanthine (an inhibitor of phosphodiesterase), and permeative adenosine 3',5'-cyclic monophosphate (cAMP) analogues potentiate the increase in cytosolic Ca2+ concentration induced by ATP. NE, forskolin, and 8-(4-chlorophenylthio)-cAMP all increase Vmax of the Ca2+ response curve of ATP. Measurement of cAMP by radioimmunoassay confirmed that the changes in the ATP response were accompanied by an increase in cAMP. These results suggest that the noradrenergic potentiation of the ATP-induced Ca2+ mobilization involves cAMP as a second messenger. Patch-clamp studies of isolated myocytes showed that neither NE nor forskolin alters the inward current elicited by ATP, but rather they increase the duration of secondary slow action potentials elicited by ATP. NE also increases the Ca2+ current through L-type Ca2+ channels in the myocytes. We conclude that NE potentiates the ATP-induced Ca2+ transient by increasing cAMP levels and that one of the early events is the increase of the inward Ca2+ current during the action potential.

Adenosine Triphosphate↗
PubMed1992

Ca2+ mobilization by extracellular ATP in rat cardiac myocytes: regulation by protein kinase C and A.

Activation of protein kinase C (PKC) modulates the mobilization of intracellular Ca2+ induced by extracellular ATP in rat ventricular myocytes. Pretreatment of myocytes with PKC activators attenuated both the ATP-induced Ca2+ transient and the noradrenergic potentiation of the Ca2+ response. Various PKC activators decreased both the basal cAMP level and the cAMP levels that had been elevated by norepinephrine, forskolin, or 3-isobutyl-1-methylxanthine. The inhibitory effects of PKC activators were reversed by the PKC inhibitor staurosporine. The ATP-induced Ca2+ response is an integrated response resulting from ATP eliciting an inward cation current (IATP), cellular depolarization, Ca2+ influx through Ca2+ channels, and Ca2+ release from the sarcoplasmic reticulum. We used the whole cell voltage-clamp technique to investigate which steps of this integrated response are affected by PKC. PKC activators did not significantly affect the IATP. In contrast, PKC activators decreased the basal Ca2+ current (ICa) or Ba2+ current and the beta-adrenergic-stimulated ICa. These results suggest that PKC-induced suppression of the ATP-induced Ca2+ response and the beta-adrenergic-potentiated Ca2+ response is achieved at least partially by decreasing the intracellular cAMP level and ICa.

Adenosine Triphosphate↗