Biomedical subjects

J Walden

Publications and source records attributed to J Walden.

At least 19 recordsLinked to original sources

PubMed1992

Calcium antagonistic effects of carbamazepine as a mechanism of action in neuropsychiatric disorders: studies in calcium dependent model epilepsies.

Carbamazepine (CBZ) is used in neurology for the treatment of epilepsies and trigeminal neuralgia and in psychiatry for the prophylactic treatment of affective and schizoaffective psychoses. Since a common mechanism of epilepsies and affective psychoses might be increased intracellular calcium ion levels, CBZ action was analyzed in penicillin, caffeine and low Mg2+ induced model epilepsies which have been shown to be suppressed specifically by organic calcium antagonists. In CA3 and CA1 areas of hippocampal slice preparations of guinea pigs CBZ reduced paroxysmal depolarizations and extracellular field potentials (EFP) in a typical time and concentration dependent manner as it is known from calcium antagonists. Furthermore, subthreshold concentrations of the organic calcium antagonist verapamil intensified the action of CBZ. NMDA induced increases of the discharge rate of EFP were, however, unaffected by CBZ.

Animals↗

PubMed1992

[Importance of calcium ions and calcium antagonists in affective psychoses].

Apart from the eminent changes in the neurotransmitter systems of the central nervous system, a disturbance of the calcium ion concentration may be of significance in the pathophysiology of affective psychoses. The present paper deals with the contribution of calcium ions in the generation of affective psychoses and discusses the calcium antagonism as a new strategy in the treatment of the disease. The following topics will be described: 1. Disturbances of calcium metabolism in affective psychoses, 2. a comparison of lithium and carbamazepine effects, 3. clinical studies with organic calcium channel blockers in affective psychoses and 4. the role of calcium ions in affective psychoses.

Affective Disorders, Psychotic↗

PubMed1992

Epileptogenesis: contributions of calcium ions and antiepileptic calcium antagonists.

The results demonstrate that organic calcium antagonists are able to reduce epileptic activity at the level of single neurons and of neuronal populations. This holds true also for human cortical tissue. Among other observations already published this justifies the hope that calcium antagonistic agents might be useful in the treatment of human epilepsies (28).

Animals↗

PubMed1991

Reduction in bioelectric GABA and NMDA responses in organotypic neocortical explants by chronic elevation of potassium.

Long-term cultures of organotypic neonatal rat neocortex slices were maintained in a serum-free medium supplemented with 25 mM potassium. Such cultures continue to be bioelectrically silent upon return to a 5 mM potassium medium. The absence of responses to pressure ejected gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) from neurons in treated explants suggests that one consequence of chronic depolarization is a reduction in the density of postsynaptic transmitter receptors. [3H]Muscimol binding to neocortical membrane preparations shows a large reduction in the binding of this agonist to GABAA receptors. These data show that the quantitative expression of at least one neurotransmitter receptor, the GABAA receptor, relies on voltage-dependent activity in developing neocortical neurons in vitro.

Action Potentials↗

PubMed1991

Sustained reduction in valvular regurgitation and atrial volumes with tailored vasodilator therapy in advanced congestive heart failure secondary to dilated (ischemic or idiopathic) cardiomyopathy.

Afterload reduction therapy can acutely improve hemodynamic function in patients with advanced heart failure; however, it is unknown if initial reductions in mitral and tricuspid regurgitation and atrial volumes can be sustained with oral therapy. Atrial volumes and atrioventricular valve regurgitation were measured using 2-dimensional and Doppler echocardiography with color-flow imaging in 14 patients with dilated heart failure (ejection fraction 17 +/- 4%) before and after 3 +/- 1 days of intensive vasodilator and diuretic therapy tailored to hemodynamic goals. Echocardiography was repeated again after 6 +/- 2 months on oral vasodilators and a flexible diuretic regimen. Acute therapy reduced systemic vascular resistance from 1,760 +/- 460 to 1,010 +/- 310 dynes.s.cm-5, pulmonary artery wedge pressure from 30 +/- 5 to 17 +/- 4 mm Hg, and right atrial pressure from 13 +/- 5 to 7 +/- 3 mm Hg, and led to a 61% increase in stroke volume (from 36 +/- 10 to 58 +/- 14 ml) (p less than 0.01). Mitral and tricuspid regurgitation, determined by color-flow fraction, initially decreased from 0.34 +/- 0.17 to 0.20 +/- 0.20 and from 0.33 +/- 0.15 to 0.13 +/- 0.13, respectively (p less than 0.001). This reduction was sustained at 6 months. Significant decreases occurred with acute therapy, with further reductions at 6 months in both mean left atrial volume (from 100 +/- 25 to 80 +/- 19 to 65 +/- 15 cm3) and right atrial volume (from 85 +/- 23 to 64 +/- 23 to 52 +/- 14 cm3) (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1991

Decrease of N-methyl-D-aspartate responses by noradrenaline in the rat motorcortex in vivo.

The influence of noradrenaline (NA) on cortical field potential changes (CFPs) induced by the glutamate subreceptor agonist N-methyl-D-aspartate (NMDA) was tested in the motorcortex of anesthetized and artificially ventilated rats. Substances were applied through a 3-barrelled micropipette by pressure ejection in different motorcortical laminae. NMDA elicited negative and NA no or small positive CFPs. Applications of NA before (up to 60 s) or overlapping the ejection of NMDA decreased the amplitude of the negative CFP induced by the excitatory amino acid. The alpha 1-adrenoceptoragonist phenylephrine mimicked the NA effect, whereas the alpha 2-adrenoceptoragonist clonidine had differential actions with decreasing and increasing NMDA elicited CFP. The beta-agonist isoproterenol was without effect. It is suggested that the diminution of NMDA effects by NA may be mediated by an intracellular pathway mechanism.

Animals↗

PubMed1991

Mechanisms underlying the generation of cortical field potentials.

The generation of currents and potentials detectable in the space surrounding cellular elements within central nervous structures is described. The following aspects are especially taken into account: Generator structures, membrane potential changes of single neurons and of single glial cells, generation of potentials in the extracellular space, and types of cortical field potentials.

Cerebral Cortex↗

PubMed1991

Parasitic diseases. Other roundworms. Trichuris, hookworm, and Strongyloides.

Trichuriasis may be asymptomatic or, in heavy infection, lead to profuse, bloody diarrhea and rectal prolapse. Diagnosis is made by finding the distinctive barrel shaped eggs in the stool or in the heavily infested patient, by anoscopy and identification of worms attached to reddened and ulcerated rectal mucosa. Mebendazole is the drug of choice in treatment. Capillariasis, a parasitic infection encountered mainly in the Philippine Islands, is of interest in that the eggs may be confused with the eggs of trichuris. Hookworm disease is generally asymptomatic, but in heavy infection, leads to iron deficiency and hypochromic, microcytic anemia. Diagnosis is made by finding the characteristic hookworm eggs on a examination of a direct fecal film. Accidental invasion of humans by dog and cat hookworm leads to cutaneous larva migrans, also known as "creeping eruption." Human hookworm is treated most effectively with mebendazole, while the rash produced by creeping eruption responds to topical thiabendazole. Strongyloides is fairly common in rural areas of the southeastern United States and may be seen in the urban setting among inmates of mental institutions, prisons, and in immigrants who formerly resided in endemic tropical regions. Because of its remarkable capacity for dissemination of larvae throughout the body, this parasite is now recognized as a serious problem for the patient who is immunocompromised. Diagnosis is made by finding larvae in the stool or by the Enterotest. All infected patients should be treated with thiabendazole. I consider the issue on Drugs For Parasitic Infections, published annually or biannually by The Medical Letter on Drugs and Therapeutics, to be the single best source of information on the treatment of parasitic diseases for primary care physicians.

Ancylostomatoidea↗

PubMed1990

Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy.

To identify patients with left ventricular ejection fractions less than 20% who are likely to survive on tailored medical therapy after referral to transplantation, this study of 152 patients addressed the hypotheses that (1) severely elevated filling pressures initially measured at referral would not necessarily predict poor outcome, (2) survival would be best when low pulmonary wedge pressures could be achieved with therapy tailored for hemodynamic goals, and (3) coronary artery disease would be an independent risk factor for early mortality. Despite an average initial ejection fraction of 0.15, cardiac index of 2.0 liters/min/m2 and pulmonary artery wedge pressure of 28 mm Hg, the actuarial survival with tailored therapy was 63% at 1 year, with 34 of 41 (83%) deaths occurring suddenly. Survival was not related to initial filling pressure elevation, but was best predicted by the pulmonary artery wedge pressures during therapy; patients achieving pressure of less than or equal to 16 mm Hg had 1-year survival of 83 vs 38% (p = 0.0001). The other independent predictors were serum sodium and coronary artery disease. Patients with high filling pressures during therapy and coronary artery disease had 21% survival at 1 year. Survival after referral to transplantation with an ejection fraction less than or equal to 20% is better than previously described. Patients in whom left ventricular filling pressures cannot be adequately reduced by tailored therapy, particularly if coronary artery disease is present, should be considered for early transplantation.

Adult↗

PubMed1990

Decrease of free calcium concentration at the outer surface of identified snail neurons during paroxysmal depolarization shifts.

Changes of free calcium concentration at the outer neuronal surface during paroxysmal depolarization shifts elicited by pentylenetetrazol were measured. Investigations were performed on the identified neuron B3 of the buccal ganglion of Helix pomatia. Extracellular calcium concentration was recorded by calcium-selective microelectrodes. The extracellular calcium concentration steeply decreased with the commencement of paroxysmal depolarization and started to reincrease when the paroxysmal depolarization had reached its plateau level. It is concluded that an influx of calcium ions takes place during paroxysmal depolarization shifts.

Animals↗

PubMed1990

Paroxysmal depolarization shifts induced by bicuculline in CA3 neurons of hippocampal slices: suppression by the organic calcium antagonist verapamil.

Organic calcium antagonists have been reported to abolish epileptic neuronal discharges elicited by pentylenetetrazol and penicillin. It was tested whether the organic calcium antagonist verapamil is able to suppress also paroxysmal depolarization shifts (PDS) induced by bicuculline. This is of special interest, since bicuculline is assumed to produce PDS by blocking GABAergic synaptic inhibition. The experiments were performed on CA3 neurons of hippocampal slices (guinea pig). Verapamil (40, 60, and 80 microM) reduced amplitude, duration and frequency of appearance of PDS until the generation of PDS failed. The results indicate that calcium currents are also involved in bicuculline PDS, and that bicuculline exerts its epileptogenic action, at least in part, on extrasynaptic sites.

Animals↗

PubMed1990

Augmentation of N-methyl-D-aspartate induced depolarizations by GABA in neocortical and archicortical neurons.

The influence of the inhibitory transmitter gamma-aminobutyric acid (GABA) on depolarizations elicited by the excitatory amino acid N-methyl-D-aspartate (NMDA) was tested in neurons of organotypic neocortical tissue cultures (newborn rat) and in CA3 neurons of the hippocampal slice (guinea pig). Drugs were applied through a 3-barrelled micropipette by pressure ejection. Applications of GABA before the ejection of NMDA increased the amplitude of the depolarizations induced by the excitatory amino acid. It is suggested that the enhancement of NMDA responses by GABA may be mainly mediated by an intracellular common pathway.

Animals↗

PubMed1990

Exercise capacity for survivors of cardiac transplantation or sustained medical therapy for stable heart failure.

Cardiac transplantation is predicted to improve survival for patients with severe symptoms of heart failure and ejection fraction of 20% or less, but the exercise capacity after cardiac transplantation is less than normal. Patients responding to vasodilators and diuretics have progressive improvement in exercise capacity despite low ejection fraction. We hypothesized that among patients currently considered appropriate for transplantation who could nonetheless subsequently be stabilized on medical therapy tailored to hemodynamic goals, survivors after 6 months of sustained medical therapy would demonstrate exercise capacity comparable to that of survivors of transplantation. Of 146 patients referred, 118 (81%) were discharged on tailored therapy without transplantation, and 88 (60%) were stable for at least 1 month. Stability after discharge was more likely in patients with lower right atrial pressures and better renal function on therapy. Of the 88 stable patients, 45 patients were listed for transplant, and 43 were ineligible or unwilling. From these patients, 42 survivors for more than 6 months follow-up after cardiac transplantation or tailoring of medical therapy underwent exercise testing. Baseline functional and hemodynamic status and left ventricular ejection fraction (15 +/- 4%) were not different between the transplant and sustained medical survivor groups at the time of initial evaluation. After 14 +/- 6 months, left ventricular ejection fraction had increased to 62 +/- 7% after transplantation (p less than 0.01) and only 22 +/- 9% after sustained medical therapy (p less than 0.05). However, there were no significant differences in the maximum workload, oxygen uptake, anaerobic threshold, or maximum oxygen pulse between survivors of cardiac transplantation and survivors on sustained medical therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Output, Low↗

PubMed1989

Augmentation of glutamate responses by GABA in the rat's motorcortex in vivo.

The influence of the inhibitory transmitter gamma-aminobutyric acid (GABA) on cortical field potential changes (CFPs) elicited by the excitatory transmitter glutamate and its subreceptor agonists N-methyl-D-aspartate (NMDA) and quisqualate was tested in the motorcortex of anesthetized and artificially ventilated rats. Drugs were applied through a 3-barrelled micropipette by ionophoresis or pressure ejection. Glutamate and its agonists evoked negative and GABA positive CFPs. Applications of GABA before (up to 300 s) the ejection of glutamate, NMDA or quisqualate increased the amplitude of the negative CFP induced by the excitatory transmitters. This augmentation was more pronounced with NMDA and quisqualate than with glutamate. It could be mimicked by the GABAA-agonist muscimol but not by the GABAB-agonist baclofen. It is suggested that the enhancement of glutamate responses by GABA may be mediated by an intracellular common pathway.

Animals↗

PubMed1989

Diverse mechanisms of unexpected cardiac arrest in advanced heart failure.

To define the mechanisms of unexpected cardiac arrest in advanced heart failure, we reviewed the causes of cardiac arrest as established from electrocardiographic monitoring and from clinical and autopsy data in patients hospitalized for cardiac transplantation evaluation and management of advanced heart failure (mean left ventricular ejection fraction, 0.18 +/- 0.08) who were stable while on vasodilator and diuretic therapy such that hospital discharge to home was anticipated. Twenty-one cardiac arrests occurred in 20 of 216 (9%) such patients during a 4-year period. Heart failure was due to coronary artery disease with prior myocardial infarction in 13 patients and nonischemic cardiomyopathy in seven patients. The rhythm at the time of arrest was severe bradycardia or electromechanical dissociation (BA/EMD) in 13 (62%) patients. The precipitating cause of the BA/EMD arrest was coronary artery thrombosis or embolism in two patients, pulmonary embolism in one patient, hyperkalemia in two patients, and unexplained hypoglycemia in one patient. In seven of 13 (54%) patients, a precipitating cause of the bradycardia arrest could not be established. Only eight of 21 (38%) arrests were due to ventricular tachycardia or fibrillation (VT/VF), and all occurred in patients with prior myocardial infarction (p = 0.02 vs. BA/EMD arrests). Two VT/VF arrests were due to acute or recent infarction, and one patient had hyperkalemia. The patients who suffered a BA/EMD arrest were similar to those who had a VT/VF arrest in age, ventricular arrhythmia history, ventricular function, and serum potassium levels. Serum sodium levels were lower in patients with BA/EMD arrests (129 +/- 3 vs. 133 +/- 4 meq/l, p = 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

[Functional implication of calcium ions in epileptic seizures. Antiepileptic effects of organic calcium antagonists].

In animal experiments, focal epileptic activity and tonic-clonic seizures were induced by local application of penicillin and repeated intraperitoneal injections of pentetrazol (PTZ), respectively. With epileptic activity neocortical and hippocampal neurons showed typical paroxysmal depolarization shifts. Experimental findings indicate that a calcium inward current and calcium dependent membrane currents participate in the generation of these events. Paroxysmal depolarizations were depressed by intra- and extracellular applications of the organic calcium channel blockers N,N-dimethyl-N-(4-cyan-4-(3,4,5-trimethoxyphenyl)-5-methyl-hexyl)- N-(beta- 3,4-dimethoxyphenylethyl)-ammonium-chloride-monohydrate (D 890) and verapamil. The same depressive effect was exerted by flunarizine in hippocampal but not in neocortical neurons. Paroxysmal depolarizations were enhanced by intracellular injections of the calcium agonist methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate (Bay K 8644) and of the calcium chelator ethyleneglycol-bis(aminoethylether)N,N,N',N'-tetraacetate (EGTA). Focal seizure activity of the neocortex was reduced and often abolished by intracerebroventricular perfusion of verapamil, with the frequency of occurrence of epileptic discharges being decreased. Generalized tonic-clonic seizures were depressed to a great extent and often abolished during an intracerebroventricular verapamil perfusion. Simultaneously, the negative shift of the DC potential evoked by the PTZ injections turned over to a positive displacement. In non-epileptic preparations, organic calcium antagonists had no depressive effects on neuronal bioelectrical activity.

Animals↗

PubMed1988

Membrane currents induced by pentylenetetrazol in identified neurons of Helix pomatia.

After systemic application of pentylenetetrazol (PTZ), mammalian as well as molluscan neurons generate epileptic paroxysmal depolarization shifts. For a further analysis of these potential oscillations the membrane currents induced by local application of PTZ onto identified neurons of Helix pomatia were investigated. Different types of responses were obtained at membrane potentials negative and positive to ca. -30 mV. At holding potentials more negative than -30 mV, PTZ as a rule evoked an inward current, sometimes preceded by a brief outward current. In a few experiments only a solitary outward current was found. The amplitudes of the inward and outward currents increased towards more negative potentials. The inward current was associated with a decrease and the outward current with an increase in membrane resistance. Besides these findings pharmacological and ion substitution experiments indicate that the inward current represents an unspecific current. At holding potentials more positive than -30 mV, PTZ evoked a sequence of currents which was the same in all neurons. This stereotyped current sequence consisted of (i) an early inward current, (ii) an intermediate outward current, and (iii) a late long-lasting inward current. The amplitudes of all these components increased towards more positive potentials with the outward current being particularly enhanced. The early inward current and the following outward current were associated with a decrease and the late inward current with an increase of the membrane resistance. Besides these pharmacological and ion substitution experiments suggest that the early inward current represents a mixed sodium and calcium current, the intermediate outward current a calcium activated potassium current. The late inward current is assumed to be due to a decreased potassium conductance. On the basis of the present results, it may be concluded that the unspecific inward current in the negative potential range is involved in the initiation and the calcium dependent potassium current in the termination of spontaneously occurring paroxysmal depolarization shifts.

Animals↗

PubMed1988

Suppression of recurrent generalized tonic-clonic seizure discharges by intraventricular perfusion of a calcium antagonist.

Epileptic depolarizations in single motor cortical and hippocampal neurons and focal epileptic discharges in neuronal cortical populations have been described to be decreased by calcium antagonists. In the present investigations the action of the calcium antagonist verapamil on generalized tonic-clonic seizures was studied. The experiments were performed in the anesthetized and artificially ventilated rat. Tonic-clonic seizures were induced by repeated intraperitoneal injections of pentylenetetrazol (PTZ). The calcium antagonist verapamil, dissolved in artificial cerebrospinal fluid, was applied to a lateral cerebral ventricle by means of the push-pull technique. This procedure achieved high concentrations of the drug in cerebral tissue and avoided alterations of the systemic circulatory system. Generalized tonic-clonic seizures were depressed in intensity to a great extent and often abolished during the verapamil perfusion. With this suppression seizures decreased in their rate of occurrence. The negative shift of the epicortical DC potential evoked by the PTZ injections before verapamil application became a positive displacement during verapamil perfusion. Control experiments revealed (i) that intraventricular perfusion with drug-free cerebrospinal fluid did not change tonic-clonic seizure activity, and (ii) that in experiments without epileptic activity verapamil perfusion exerted no depressive effect on the power of the spontaneous EEG and failed to shift the DC potential to the positive side. As a whole, systemic administration of the calcium antagonist verapamil depressed tonic-clonic seizures and did not depress non-epileptic cerebral activity.

Animals↗