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Biomedical subjects

C M Lathers

Publications and source records attributed to C M Lathers.

At least 73 records · Page 4Linked to original sources
PubMed1984

Modulation of presynaptic gamma aminobutyric acid release by prostaglandin E2: explanation for epileptogenic activity and dysfunction in autonomic cardiac neural discharge leading to arrhythmias?

Sudden unexplained death accounts for 5-17% of deaths in the epileptic population. It has no known etiology by definition but autonomic dysfunction has been mentioned as a possible progenitor. A review of the literature was begun to ascertain a possible mechanism by which epileptogenic activity and autonomic dysfunction may be induced in these patients. Prostaglandin E2 is implicated as a possible gamma aminobutyric acid neurotransmitter inhibiting agent responsible for epileptogenic activity and autonomic dysfunction leading to arrhythmias in epileptic patients who suddenly die from unexplainable causes.

Animals↗
PubMed1983

Cardiac neural discharge and epileptogenic activity in the cat: an animal model for unexplained death.

This study developed an animal model to explore the hypothesis that altered autonomic function may be one cause for unexplained sudden epileptic deaths. After alpha-chloralose anesthesia, 9 cats received a tracheostomy and a thoracotomy. Intravenous gallamine was used to paralyze the cats. Blood pressure, arterial blood gases, electrocardiogram, and rectal temperature were monitored. Simultaneous monitoring of the neural discharge in postganglionic cardiac sympathetic branches and the vagus nerve was combined with a bilateral craniectomy and electrocorticography. Pentylenetetrazol was given intravenously at 10 min intervals in 10, 20, 50, 100, 200, and 2000 mg/kg doses. Epileptiform discharges were categorized as a prolonged ictal (duration of 10 sec or more), brief ictal (duration of less than 10 sec mixed with suppression), and interictal spike activity. The two types of ictal activity were quantified by duration in seconds for the 10 min interval after each dose of pentylenetetrazol; the number of interictal spikes/min was determined for each minute of the entire experiment. This study developed a model which quantified the degree of epileptiform activity and correlated it with changes in cardiovascular function and autonomic cardiac neural discharge. An imbalance within and between sympathetic and parasympathetic cardiac neural discharges was found, as was a significant disruption of the physiological relationships between heart rate and blood pressure. Frequent and varied electrocardiogram abnormalities occurred. All of the above changes occurred during minimal (interictal) subconvulsant as well as during maximal (ictal) convulsant epileptogenic activity.

Animals↗
PubMed1983

Failure of methylprednisolone to prevent nonuniform cardiac accelerator nerve discharge associated with coronary occlusion-induced arrhythmia: evidence against prostaglandin modulation of autonomic cardioaccelerator neural discharge in the anesthetized cat.

Postganglionic cardiac sympathetic neural discharge in the minute prior to arrhythmia produced by acute occlusion of the left anterior descending coronary artery was nonuniform, i.e., both increases or decreases occurred. It is hypothesized that the nonuniform neural discharge is transmitted to the heart, causing nonuniform changes in excitability and conduction which produce ventricular arrhythmias. Prostaglandins have been shown to exhibit both arrhythmogenic as well as antiarrhythmic actions. Methylprednisolone (30 or 50 mg/kg, i.v., a known inhibitor of prostaglandin synthesis) was given 30 minutes prior to coronary occlusion of the left anterior descending artery. Both doses of methylprednisolone failed to: exert any effect on the mean postganglionic cardiac sympathetic nerve discharge prior to coronary occlusion; eliminate the nonuniform neural discharge associated with occlusion-induced arrhythmia; increase the time to arrhythmia or death; and decrease the number of cats dying after acute coronary occlusion. Thus, it is hypothesized that methylprednisolone failed to prevent the arrhythmogenic actions of prostaglandins. The failure of methylprednisolone to decrease the time to arrhythmia suggests that, in this study, an antiarrhythmic mechanism for prostaglandins does not exist. The failure of methylprednisolone to prevent the occlusion-induced nonuniform cardiac sympathetic discharge suggests that prostaglandin modulation of the autonomic balance on the heart is not due to a direct action on the postganglionic cardiac sympathetic nerve.

Adrenergic Fibers↗
PubMed1982

Lack of effect of methylprednisolone on cardiac neural discharge associated with coronary occlusion-induced arrhythmia and death.

Methylprednisolone (30 or 50 mg/kg i.v.) was given 30 min prior to acute coronary occlusion of the left anterior descending artery. Neither dose of methylprednisolone exerted any effect on the mean postganglionic cardiac sympathetic nerve discharge prior to coronary occlusion and did not eliminate the nonuniform i.e., increased and/or decreased, neural discharge associated with occlusion-induced arrhythmia. Pretreatment with methylprednisolone did not increase the time to arrhythmia or death and did not decrease the number of cats dying after acute coronary occlusion.

Analysis of Variance↗
PubMed1982

Autonomic dysfunction in epilepsy: characterization of autonomic cardiac neural discharge associated with pentylenetetrazol-induced epileptogenic activity.

The purpose of this study was to determine if epileptogenic activity is associated with changes in autonomic cardiac neural discharge and the development of arrhythmias. Nine cats, anesthetized with alpha-chloralose, received pentylenetetrazol (PTZ), 10, 20, 50, 100, 200, and 2,000 mg/kg, intravenously at 10 min intervals. The following were monitored: neural discharge from 1 to 3 postganglionic cardiac sympathetic branches (8 cats, 17 nerves) and the vagus (7 cats, 8 nerves); the electrocorticogram; blood pressure; heart rate; and lead II electrocardiogram. Autonomic dysfunction was manifested by: the observation that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure; the development of a marked increase in variability in mean autonomic cardiac sympathetic and parasympathetic neural discharge; and the fact that the very large increase in the variability of the discharge rate of parasympathetic nerves was seen after PTZ, 50 mg/kg, but did not develop until 100 mg/kg in sympathetic neural discharge. This autonomic imbalance was associated with both interictal and ictal epileptogenic activity. Almost invariably, interictal discharge occurred after PTZ, 10 mg/kg; with higher doses, the duration of ictal activity increased although interictal discharges were present. The altered cardiac autonomic neural discharge was associated with minimal epileptogenic activity in the form of interictal discharges and cardiac arrhythmias which may contribute to sudden unexplained death of the epileptic.

Animals↗
PubMed1981

The action of reserpine, 6-hydroxydopamine, and bretylium on digitalis-induced cardiotoxicity.

This study determined whether the protective effect of reserpine against ouabain-induced ventricular arrhythmias in the cat is due to an action of the drug on the adrenergic nerve terminal. Reserpine (5 mg/kg i.p.) administered 24 h prior to ouabain (2 micrograms/kg per min i.v., until death) increased the dose of ouabain to produce premature ventricular contractions, ventricular tachycardia, and death from 77.3 +/- 5.2 to 105.0 +/- 6.0; 84.9 +/- 5.2 to 132.7 +/- 9.1; and 108.8 +/- 4.0 to 165.7 +/- 10.4 micrograms/kg, respectively (P less than 0.05). When 6-hydroxydopamine (6OHDA; 20 mg/kg i.v.) was given 3 days prior to the experiment, the protective effect of reserpine was not evident. When bretylium (20 mg/kg i.v., 2 h prior to ouabain) was administered to animals previously treated with reserpine, the dose of ouabain which produced premature ventricular contractions, ventricular tachycardia, and death was increased to 109.0 +/- 7.2; 146.1 +/- 12.6; and 165.8 +/- 7.6 micrograms/kg, respectively (P less than 0.05). However, the magnitude of this protective action was similar to that produced by reserpine alone. Lathers et al. (Fed. Proc. 40, 672, 1981) reported that bretylium alone provides protection of a similar order of magnitude as reserpine. Thus, the effects of reserpine and bretylium were not additive; this indicates that the two agents may be acting on the same locus or they may be acting at different sites with the action of one drug masking or blocking the action of the other. Since 6OHDA prevented the action of reserpine on ouabain-induced ventricular arrhythmia and since 6OHDA only produces degeneration of adrenergic nerve terminals, it is probable that the protective effect of both reserpine and bretylium is due to an action at the adrenergic nerve terminal. The heart rate and blood pressure were not involved in the antiarrhythmic effects of reserpine.

Animals↗
PubMed1980

Effect of timolol on autonomic neural discharge associated with ouabain-induced arrhythmia.

The purpose of this study was to determine the effect of the beta-blocking agent timolol on postganglionic cardiac and preganglionic splanchnic sympathetic and vagal neural discharge, ouabain-induced arrhythmia, heart rate and mean arterial blood pressure. Cats were anesthetized with alpha-chloralose, given atropine, and pretreated with timolol (5 mg/kg, i.v. infused at a rate of 0.5 mg/kg/min for 10 min). Bolus injections of ouabain (25 microgram/kg, i.v.) were given every 15 min until the animals died; the first injection was given 15 min after the end of the timolol infusion. When compared with cats (n = 13) receiving only ouabain, timolol (n = 11 cats) increased the time to ouabain-induced arrhythmia and death from 23 +/- 3 to 48 +/- 7 and 46 +/- 3 to 76 +/- 9 min, respectively (p less than 0.05). Both heat rate and mean arterial blood pressure had decreased from 137 +/- 4 to 104 +/- 6 beats/min and 133 +/- 6 to 103 +/- 7 mm Hg, respectively (P less than 0.05); ouabain did not reverse the decreases. Neural activity monitored from the vagus and from the postganglionic cardiac and preganglionic splanchnic sympathetic nerves was not significantly altered by the infusion of timolol. The administration of ouabain after timolol did not alter splanchnic nor vagal discharge. Most important was the observation that postganglionic cardiac sympathetic neural discharge exhibited both increases and decreases, i.e., a nonuniform neural discharge, at the time of ouabain-induced arrhythmia and that the ouabain-induced nonuniformity did not occur in the cats pretreated with timolol. Thus, the protective effect of timolol may be due, in part, to prevention of the nonuniform postganglionic cardiac sympathetic neural discharge and to the prevention of ouabain-induced increases in vagal discharge. The establishment of beta-blockade and a direct negative inotropic action may also have contributed to the antiarrhythmic action of timolol.

Animals↗
PubMed1978

Nonuniform cardiac sympathetic nerve discharge: mechanism for coronary occlusion and digitalis-induced arrhythmia.

This study examined nonuniform postganglionic cardiac sympathetic neural discharge as a possible mechanism involved in the production of coronary occlusion or ouabain-induced arrhythmias. After acute occlusion of the left anterior descending coronary artery in 12 cats, anesthetized with alpha-chloralose and pretreated with atropine, arrhythmia occurred within 3 min in eight animals; three of these died in ventricular fibrillation. In recordings from 15 nerves in the eight animals with arrhythmia, spontaneous discharge increased in nine nerves, decreased in five nerves, and showed no change in one nerve. This nonuniform neural discharge was associated with the development of arrhythmia after occlusion. In four of the cats, neural discharge did not change within the first 3 min after coronary artery occlusion and arrhythmia did not occur. Development of ouabain-induced arrhythmia was accompanied by a nonuniform pattern in the neural discharge (13 cats). This discharge may alter ventricular excitation and conduction to produce arrhythmia.

Action Potentials↗
PubMed1976

Ethanol effects on muscle spindle afferent activity and spinal reflexes.

The effects of ethanol on muscle spindle afferent activity and on the mono- and polysynaptic reflexes were examined in cats. Ethanol was administered incrementally as intravenous infusions of 0.7 g/kg of ethanol 30 minutes apart; mean arterial blood alcohol concentrations reached 30 minutes after the first and fourth infusions were 1.1 and 3.8 mg/ml, respectively. Ethanol produced modest, dose-related increases in the afferent activity from muscle spindles in spinal- and pentobarbital-anesthetized cats. Mean phasic and static discharge frequencies were both increased approximately 10 impulses/sec after infusions of a total of 2.8 g/kg. In unanesthetized animals, comparable blood levels of ethanol were associated with mild to marked motor incoordination. The mean amplitudes of the mono- and polysnaptic reflexes in spinal animals, elicited with supramaximal single shocks to the muscle nerve, were depressed to 92 and 84% of control levels, respectively, after 0.7 g/kg and continued to fall to 50 and 60% of control levels after 2.8 g/kg of ethanol. Ethanol failed to depress preferentially polysynaptic reflexes. It is concluded that the spindle afferent excitation was involved in the motor effects of ethanol but that it was insufficient to explain fully the skeletomotor alterations produced by ethanol; rather, ethanol actions at peripheral and spinal and, perhaps, supraspinal sites all appear to be involved in ethanol-induced impairment of motor function.

Achilles Tendon↗
PubMedDate not supplied

The effect of C1 spinal cord transection or bilateral adrenal vein ligation on thioridazine-induced arrhythmia and death in the cat.

The phenothiazine thioridazine 1 mg/kg/min was infused intravenously into three groups of cats: (1) thioridazine alone (N = 5), (2) after bilateral adrenal ligation (N = 4), and (3) after spinal cord section at the atlanto-occipital junction (C1; N = 6). The times to arrhythmia and death with thioridazine alone were 47.8 +/- 7.8 and 72.8 +/- 5.6 minutes respectively. After bilateral adrenal ligation, arrhythmia and death occurred at 41.1 +/- 5.2 and 53.1 +/- 5.8 minutes, respectively, which showed no increase (P greater than .05) from thioridazine alone. After spinal cord section, thioridazine-induced arrhythmia and death occurred at 74.0 +/- 13.7 and 85.7 +/- 13.8 minutes, respectively, which were not increased (P greater than .05) when compared with thioridazine alone. The results of this study suggest that neither adrenomedullary catecholamines nor the central sympathetic component above C1 plays a significant role in acute thioridazine-induced arrhythmia. The action of thioridazine to induce arrhythmia in spite of transection of the spinal cord or bilateral adrenal vein ligation suggests that its cardiotoxicity is a result of a direct myocardial effect. Thioridazine depressed blood pressure without producing the sustained reflex tachycardia normally seen with hypotension. This suggests that the agent may modify the baroreceptor reflex arc.

Adrenal Medulla↗
PubMedDate not supplied

Review of autonomic dysfunction, cardiac arrhythmias, and epileptogenic activity.

Similarities in autonomic dysfunction associated with arrhythmias and death in animal models for digitalis toxicity, myocardial infarction, psychotropic toxicity, and epileptogenic activity are reviewed. When intravenous (IV) pentylenetetrazol was given to anesthetized cats, autonomic dysfunction was associated with both interictal and ictal epileptogenic activity. The autonomic dysfunction was manifested by the fact that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure, the development of a marked increase in variability in mean autonomic cardiac nerve discharge, and the appearance of a very large increase in the variability of the discharge rate of parasympathetic nerves first and then secondly in sympathetic discharge. The altered autonomic cardiac nerve discharge was associated with interictal epileptogenic activity and arrhythmia, which may contribute to sudden unexplained death in patients with epilepsy. Since phenobarbital (20 mg/kg, IV 60 min prior to pentylenetetrazol) exhibited anticonvulsant, but not antiarrhythmic and neural depressant activity, phenobarbital does not appear to be the ideal agent to prevent the autonomic dysfunction associated with epileptogenic activity in this animal model.

Arrhythmias, Cardiac↗
PubMedDate not supplied

Anticonvulsant and antiarrhythmic actions of the beta blocking agent timolol.

Cats were anesthetized with alpha-chloralose and pentylenetetrazol, 10 and/or 20 mg were administered intracerebroventricularly (i.c.v.) to elicit epileptiform activity, including both interictal and ictal discharges. Timolol, 10, 100, 500 micrograms/kg i.c.v. and 1, 5, 10 and/or 20 mg/kg i.v., was administered at 5 min intervals to determine whether it suppressed the epileptiform activity. Mean arterial blood pressure and heart rate increased after the administration of pentylenetetrazol; these increases were associated with the development of epileptiform activity and cardiac arrhythmias. All doses of timolol caused a decrease in the blood pressure and heart rate elevated by pentylenetetrazol and suppressed the epileptiform activity. Similar findings were obtained in cats that received the same doses of timolol administered at different time intervals. The data indicate that the central administration of timolol reverses the epileptiform activity of pentylenetetrazol in the brain and suppresses the associated increases in blood pressure, heart rate and cardiac arrhythmias.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Paroxysmal autonomic dysfunction, epileptogenic activity and sudden death.

Transient abnormalities of autonomic nervous system function are observed during almost every generalized tonic-clonic seizure and include disruptions in blood pressure, cardiac arrhythmias and apnea. An increasing body of literature indicates that epileptogenic discharges, even without accompanying clinical seizure activity, can produce a spectrum of autonomic abnormalities. Marked changes in blood pressure and cardiac rhythm occur in patients paralyzed with neuromuscular blocking agents and subjected to electrical shock or intravenous pentylenetetrazol. Similar changes are observed in patients with focal temporal lobe discharges. There is also experimental evidence suggesting that in addition to the well known effects of generalized seizure discharges, interictal discharges can produce effects upon the cardiovascular system. Neurogenic pulmonary edema may be another autonomic dysfunction associated with seizures. The phenomenon of unexplained sudden death in persons with epilepsy, which accounts for up to 15% of mortality in this group, may be a result of some unexplained irreversible disruption of autonomic homeostasis in the face of all these forces of electrical disorganization. Paradoxically, some persons manifest cardiovascular autonomic dysfunction with consequent seizures which are phenomenologically very similar to those of cerebral origin. It is important to consider performing Holter monitoring in patients with epilepsy of unknown cause and 24 h ambulatory electroencephalograms in patients with unexplained cardiac arrhythmias.

Autonomic Nervous System Diseases↗
PubMedDate not supplied

A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

Animals↗
PubMedDate not supplied

Role of the adrenergic nerve terminal in digitalis-induced cardiac toxicity: a study of the effects of pharmacological and surgical denervation.

This study determined whether the protective action of bretylium against ouabain-induced ventricular arrhythmia in the cat is related to an action of bretylium on the adrenergic nerve terminal. Bretylium pretreatment (20 mg/kg, i.v.) administered 2 h prior to ouabain (2 micrograms/kg/min, i.v. until death) increased the dose of ouabain to produce premature ventricular contraction, ventricular tachycardia, and death from 77.2 +/- 5.2 to 107.7 +/- 6.7 micrograms/kg; from 84.9 +/- 5.2 to 113.9 +/- 7.1 micrograms/kg; and from 108.8 +/- 4.0 to 146.7 +/- 5.7 micrograms/kg, respectively (p less than 0.05). Surgical denervation 2 weeks prior to the experiment or 6-hydroxydopamine (6OH dopamine), 20 mg/kg, i.v., administered 3 or 14 days prior to the ouabain infusion did not protect against the arrhythmogenic effects of ouabain. When bretylium was administered to cats pretreated with 6OH dopamine 3 days prior to the ouabain infusion or to surgically denervated cats, the protective action against ouabain-induced arrhythmia did not develop. Since 6OH dopamine and surgical denervation prevented the action of bretylium on ouabain-induced ventricular arrhythmia, it appears that bretylium is acting on the adrenergic nerve terminal. Thus, agents like bretylium that act on the adrenergic nerve terminal, leaving it structurally intact but not functional, are effective against ouabain-induced ventricular arrhythmia while procedures which cause the degeneration of the adrenergic nerve terminal, such as 6OH dopamine and surgical denervation, are not. These observations indicate that for the protective effect of sympathectomy against ouabain-induced arrhythmia to develop, the adrenergic nerve terminal must be present, although not functional as far as adrenergic neurotransmission is concerned. Changes in the heart rate or blood pressure did not appear to be a factor in the protective effect of bretylium.

Animals↗