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Biomedical subjects

M J McLean

Publications and source records attributed to M J McLean.

At least 73 records · Page 4Linked to original sources
PubMed1986

Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture.

Effects of the anticonvulsant drugs sodium valproate (NaVP) and ethosuximide (ES) on mouse central (spinal cord and cortical) neurons in primary dissociated cell culture were studied using intracellular recording techniques. Drug effects on two properties of the neurons were assayed: the ability to sustain high frequency repetitive firing (SRF) of sodium-dependent action potentials, a voltage sensitive nonsynaptic membrane property; and the amplitude of responses to iontophoretically applied gamma-aminobutyric acid (GABA), a postsynaptic effect of this inhibitory amino acid neurotransmitter. At concentrations equivalent to the clinically useful therapeutic range in cerebrospinal fluid (6-200 microM), NaVP limited SRF to a few action potentials in both spinal cord and cortical neurons during long (450 msec) depolarizing current pulses. The limitation of SRF was paralleled by use-dependent reduction of maximal rate of rise (Vmax) of the action potentials and prolongation of recovery of Vmax from inactivation. This action was similar to limitation of SRF produced by phenytoin and carbamazepine. The 2-en-metabolite of NaVP, sodium 2-propyl, 2-pentenoate, did not limit SRF at 12 to 120 microM. However, the diphenyl analog of NaVP, sodium diphenylacetate, limited SRF at concentrations between 4.7 to 23.5 microM. ES did not affect SRF at concentrations up to 700 microM. At concentrations of 120 to 1000 microM, including the upper limit of therapeutic range, NaVP did not affect postsynaptic GABA responses in 80% of spinal cord neurons. In the remaining 20%, GABA responses were augmented less than 33%. ES reduced slightly (22%) GABA responses at a high concentration (700 microM). These findings suggest that limitation of SRF may be an important cellular mechanism by which NaVP, but not ES, exerts anticonvulsant efficacy and that neither ES nor NaVP have anticonvulsant action by enhancing postsynaptic GABA action.

Action Potentials↗
PubMed1985

Anticonvulsant drug mechanisms of action.

The effects of clinically used anticonvulsant drugs on high-frequency sustained repetitive firing (SRF) of action potentials and on postsynaptic responses to iontophoretically applied gamma-aminobutyric acid (GABA) have been compared to establish a classification of anticonvulsant drugs based on cellular mechanisms of action. By using concentrations in the range of therapeutic cerebrospinal fluid values in humans, drugs have been separated into three categories: Phenytoin, carbamazepine, and valproic acid limited SRF, but did not alter GABA responses. Phenobarbital, clonazepam, and diazepam augmented GABA responses and limited SRF only at concentrations above the therapeutic range in ambulatory patients but that are achieved in the acute treatment of status epilepticus. Ethosuximide failed to affect SRF or GABA responses even at supratherapeutic concentrations. Ability of an anticonvulsant to limit SRF correlated well with efficacy against generalized tonic-clonic seizures clinically and against maximal electroshock seizures in experimental animals. Augmentation of GABA responses and lack of limitation of SRF correlated with efficacy against generalized absence seizures in humans and against pentylenetetrazol-induced seizures in animals. However, ethosuximide must act against generalized absence seizures and against pentylenetetrazol-induced seizures by a third, as yet unknown, mechanism. Other actions occurring at supratherapeutic concentrations correlated with clinical toxicity.

Action Potentials↗
PubMed1985

Cellular mechanistic bases for classification of clinically useful anticonvulsant drugs.

Anticonvulsant drug effects on mammalian central neurons in primary cell cultures were investigated. The concentrations at which these drugs limited repetitive firing of action potentials were measured. Their effects on postsynaptic responses to iontophoretically applied GABA were also compared. Based on effects of anticonvulsant drugs on in-vitro assays and action on seizures in man and experimental animals, a classification of clinical anticonvulsants is proposed based on cellular mechanisms of action. Three categories are identified. The mechanisms of action at the cellular level may be useful in predicting clinical efficacy of anticonvulsants under development. The concentration dependence of the in-vitro actions may predict further the therapeutic range of the drug and the mechanisms associated with clinical toxicity.

Animals↗
PubMed1985

Treatment of acute deficits of moyamoya disease with verapamil.

A 7 year old girl with moyamoya disease presented with progressive right arm and leg weakness and muteness. Intravenous administration of verapamil was followed by immediate and lasting improvement in motor function and return of some expressive language. A second infusion of verapamil during angiography produced an increased opacification of collateral vessels in the left basal ganglia, suggesting drug-induced vasodilation and reversal of ischaemia as a mechanism for the observed clinical improvement. Calcium-channel blockers may be useful in the acute management of selected patients with moyamoya disease.

Arterial Occlusive Diseases↗
PubMed1984

Diazepam and its anomalous p-chloro-derivative Ro 5-4864: comparative effects on mouse neurons in cell culture.

The actions of diazepam and its p-chloro-derivative Ro 5-4864 were compared on mouse spinal cord and dorsal root ganglion neurons in cell culture. Diazepam enhanced but Ro 5-4864 reduced iontophoretic GABA responses in a concentration-dependent manner. Both diazepam and Ro 5-4864 limited sustained, high frequency repetitive firing of spinal cord neurons but diazepam was more potent. Ro 5-4864 was, however, more potent than diazepam in inhibiting spontaneous neuronal activity of spinal cord neurons and reducing the duration of calcium-dependent action potentials of dorsal root ganglion neurons. The differing actions of diazepam and Ro 5-4864 may account for the contrasting pharmacological spectra of the two benzodiazepines.

Animals↗
PubMed1983

Multiple actions of phenytoin on mouse spinal cord neurons in cell culture.

Concentration-dependence of multiple actions of phenytoin (PT) on mouse spinal cord neurons in primary dissociated cell culture was studied using intracellular microelectrode recording techniques. At concentrations of 2 to 50 micrograms/ml, PT did not alter resting membrane potential or input resistance. At 1 to 2 micrograms/ml, equivalent to therapeutic cerebrospinal fluid concentrations, PT limited the ability to sustain high-frequency repetitive firing of action potentials during long (500-2000 msec) depolarizing current pulses. There was a progressive reduction of maximal rate of rise (Vmax) of action potentials during the train until firing failed. Recovery of Vmax of single action potentials after repetitive firing was also prolonged. PT did not reduce Vmax of a single action potential at 1 to 2 micrograms/ml, but did so at 3 to 40 micrograms/ml in a voltage-dependent manner. Hyperpolarization partially reversed this reduction of Vmax. Thus, PT may slow recovery of sodium channels from inactivation. At concentrations above 3 micrograms/ml, PT reduced spontaneous neuronal firing with progressive increase in the number of quiescent neurons, reduced calcium-dependent action potential duration and amplitude, eradicated convulsant-induced paroxysmal bursting and augmented postsynaptic responses to iontophoretically applied gamma-aminobutyric acid. Glutamic acid responses were unaffected at PT concentrations of 10 micrograms/ml or less. These actions occurred at concentrations equivalent to toxic cerebrospinal fluid levels in patients and may be related to PT-induced toxicity. We suggest that limitation of sustained high-frequency repetitive firing may account, at least in part, for the anticonvulsant efficacy of PT.

Action Potentials↗
PubMed1979

Electrophysiological recordings from spontaneously contracting reaggregates of cultured smooth muscle cells from guinea pig vas deferens.

Smooth muscle cells were enzymatically dispersed from vasa deferentia of adult male guinea pigs (250-400 g). These cells reassociated in vitro to form monolayers and small spherical reaggregates (0.05-0.3 mm in Diam). Within 48 h of being placed in culture, cells in both types of preparation began to contract spontaneously. The contractions were rhythmic and slow. Cells in the monolayers stopped contracting after approximately 1 wk in vitro, but the reaggregates continued to contract spontaneously for at least 3 wk. Electron microscopy of the reaggregates revealed the presence of thick and thin myofilaments. Overshooting action potentials were recorded in many of the cells penetrated (primarily in reaggregates), and were accompanied by visible contractions of the aggregate or monolayer. Quiescent cells could often be excited by intracellularly applied depolarizing and hyperpolarizing (anodal-break) current pulses. The resting potentials had a mean value of -58 +/- 2 mV. The action potentials were usually preceded by a spontaneous depolarization. The action potentials had slow rates of rise (1--4 V/s) which were unaffected by tetrodotoxin (TTX, 1 microgram/ml), a known blocker of fast Na+ -channels. Verapamil (1 microgram/ml) blocked the action potentials. The mean value of input resistance was 6.9 +/- 0.5 M omega (n = 12). These electrophysiological properties are similar to those of intact adult vas deferens smooth muscle cells. Thus, the cultured adult vas deferens smooth muscle cells retain their functional properties in vitro even after long periods.

Action Potentials↗
PubMed1977

Prognostic factors in small malignant melanomas of choroid and ciliary body.

Two hundre seventeen small malignant melanomas, each with a volume less than 1,400/cu mm, were studied to determine what factors were useful in predicting metastasis. Using a single-factor approach with 16 risk factors, we found seven that correlated well with outcome. These were cell type, pigmentation, size (largest dimension), scleral extension, mitotic activity, location of anterior margin of the tumor, and optic nerve extension. Using a linear discriminant function, the four best factors in combination were cell type, largest dimension, scleral extension, and mitotic activity. Four variables (largest diameter, location of anterior margin, mitotic activity, and optic nerve invasion) that might be correlated with clinical observations were found to be less accurate in separating fatal and nonfatal cases than cell type alone.

Adult↗
PubMed1976

Messenger RNA induction of fast sodium ion channels in cultured cardiac myoblasts.

Incubation with adult heart messenger RNA caused the appearance of fast sodium ion channels in young myocardial cells whose development has been arrested in vitro. The induction was blocked by cycloheximide, indicating dependence on protein synthesis. Thus, cardiac myoblasts can be made to differentiate in vitro, and membrane properties can be altered by exogenous RNA.

Action Potentials↗
PubMed1976

Mechanism for the postive inotropic effect of angiotensin II on isolated cardiac muscle.

Angiotensin II (A II) and analogues were tested for their ability to restore electrical and mechanical activity to cardiac muscle preparations in which the fast Na+ channels had been inactivated by partial depolarization (22-27 mM K+) or by tetrodotoxin (TTX). The partially depolarized or TTX-blocked preparations were chosen because under these conditions electrical and mechanical responses are primarily Ca2+ -dependent. In depolarized rabbit right atria, A II restored spontaneous mechanical and electrical activity (measured by both intracellular and extracellular recording techniques). The frequency of action potential discharge was concentration-dependent; the threshold concentration of A II was 10(-10) M, the ED50 was 8 X 10(-9) M, and the maximum effect was observed at 5 X 10(-8) M. In contrast, depolarized guinea pig atria were insensitive to A II, Sar1-angiotensin II, and des-Asp1-angiotensin II, even at concentrations as high as 10(-5) M. Rabbit papillary muscle (TTX-blocked), embryonic (18-day) chick heart (partially depolarized) and chick heart reaggregates (TTX-blocked) responded similarly to rabbit atria in that A II (9.6 X 10(-7) M) restored both electrical and mechanical activity. We found that in these preparations the action of A II was unaffected by propranolol (5.0 X 10(-6) M to 5.0 X 10(-5) M) but was blocked by Mn2+ (10(-3) M), D-600 (1 X 10(-7) g/ml) and the specific A II antagonists Sar1-Ala8-angiotensin II (P-113) (5.0 X 10(-5) M) and Sar1-Ile8-angiotensin II (5.28 X 10(-5) M). We conclude that the positive inotropic effect of A II on the myocardium is due to its ability to increase transmembrane ion movements in or through the cell membrane. The ability of Mn2+ and D-600 to block this effect suggests that this ion movement is via the so-called "slow channels."

Action Potentials↗