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M A Rogawski

Publications and source records attributed to M A Rogawski.

At least 109 records · Page 6Linked to original sources
PubMed1987

Colchicine myopathy and neuropathy.

Although colchicine has been used for centuries, its neuromuscular toxicity in humans is largely unrecognized. In this report we describe a characteristic syndrome of myopathy and neuropathy and present 12 new cases of the condition. Colchicine myopathy may occur in patients with gout who take customary doses of the drug but who have elevated plasma drug levels because of altered renal function. It usually presents with proximal weakness and always presents with elevation of serum creatine kinase; both features remit within three to four weeks after the drug is discontinued. The accompanying axonal polyneuropathy is mild and resolves slowly. Electromyography of proximal muscles shows a myopathy that is marked by abnormal spontaneous activity. Because of these features, colchicine myoneuropathy is usually misdiagnosed initially, either as probable polymyositis or as uremic neuropathy. The myopathy is vacuolar, marked by accumulation of lysosomes and autophagic vacuoles unrelated to necrosis or to the mild denervation in distal muscles. The morphologic changes in muscle suggest that the pathogenesis involves disruption of a microtubule-dependent cytoskeletal network that interacts with lysosomes. Correct diagnosis may save patients with this disorder from inappropriate therapy.

Action Potentials↗
PubMed1987

Electrical properties of cultured human adrenocorticotropin-secreting adenoma cells: effects of high K+, corticotropin-releasing factor, and angiotensin II.

ACTH-secreting pituitary adenoma cells were cultured from specimens obtained by transphenoidal hypophysectomy in five patients with Cushing's disease. The majority of adenoma cells (90%) stained specifically with antiserum against human ACTH. The electrophysiological properties and response to hormones of these cells were studied with intracellular recording techniques under current clamp and voltage clamp conditions. Most (80%) of the cells fired action potentials that were Ca2+-dependent inasmuch as they were blocked by Co2+ (5 mM) and by removal of Ca2+ from the medium, but were unaffected by tetrodotoxin (0.3 mM) and by Na+ removal. The cells responded to factors known to stimulate ACTH release, including high K+, CRF, and angiotensin II (AII). High K+ (50 mM) induced a membrane depolarization in association with an increase in conductance. CRF (100 nM) produced a depolarization, a decrease in conductance, an increase in spike firing, and an increase in spike duration. Although AII was inactive in ordinary recordings, in cells loaded with lithium (Li+) to promote the phospholipid-dependent second messenger system, the peptide produced an increase in spike firing and spike duration with no change in membrane potential. The combination of CRF and AII (CRF + AII; 100 nM each) in Li+-loaded cells caused a greater excitatory effect than either peptide alone. Under voltage clamp, the response either to CRF or to CRF + AII could be attributed, at least in part, to the inhibition of a slow, voltage-dependent K+ current that is persistently active at resting potential. These results indicate that modulation of action potential firing may be an early step in the regulation of ACTH release from pituitary cells by known secretagogues. Since action potentials in these cells are associated with Ca2+ entry, the resulting changes in intracellular Ca2+ levels could mediate the effects of the hormones on secretion.

Action Potentials↗
PubMed1986

Single voltage-dependent potassium channels in cultured rat hippocampal neurons.

Single-channel recordings using the gigohm seal patch-clamp technique were carried out on the somatic membranes of dissociated embryonic rat hippocampal neurons grown in cell culture. The recording medium contained tetrodotoxin to block the voltage-dependent Na+ conductance and Cd2+ to block Ca2+ and Ca2+-activated conductances. In the cell-attached configuration, depolarizing voltage steps activated outward directed single-channel currents with conductance 15-20 pS. The channel openings exhibited a moderate degree of flickering. The mean burst lifetimes ranged from 5 to 13 ms with a tendency to increase slightly at more depolarized potentials (T = 21-25 degrees C). Reversal potential measurements using excised membrane patches indicated that the channels behaved as expected of a K+-selective membrane pore. Channel opening occurred in Ca2+-free EGTA-containing solutions but was never observed in the presence of tetraethylammonium (TEA; 20 mM). The frequency of channel opening increased as the membrane was depolarized by up to 50 mV from resting potential; the fraction of time spent in the open state during the first 300 ms following a step depolarization increased e-fold for a 8-25 mV change in potential. First-latency histograms and simulations of the macroscopic current based on channel data obtained during repeated depolarizing voltage steps indicated that the probability of the channel being in the open state increases gradually with time after a step depolarization. During repeated depolarizing steps the channels appeared to randomly enter and exit a long-lived inactive state. It is concluded that these channels may underly the slowly activating, very slowly inactivating, TEA-sensitive voltage-dependent K+ current (IK) in cultured hippocampal neurons.

Animals↗
PubMed1984

A transient potassium conductance regulates the excitability of cultured hippocampal and spinal neurons.

Cultured mouse spinal cord and rat hippocampal neurons were voltage clamped with a two-electrode system in the presence of tetrodotoxin (1 to 3 microM) and tetraethylammonium (25 mM). Depolarizing voltage commands from holding potentials negative to -50 mV evoked a transient outward current response that peaked within 10 msec and decayed exponentially with a time constant of 10 to 40 msec. The current was inactivated by holding at potentials more positive than -50 mV but could be reactivated by brief hyperpolarizing prepulses (20-msec steps to -90 mV reactivated 50%). The inversion potential of the tail current evoked in a double-step protocol was -70 to -75 mV, and this shifted in a depolarizing direction with elevated [K+]0. The transient outward current was blocked by external application of 4-aminopyridine (4-AP) with an IC50 of 2 mM. In experiments under current clamp, 4-AP suppressed an initial transient rectification of the electrotonic potential recorded in response to depolarizing current and reduced the threshold for single and repetitive action potentials. Thus, a transient K+ conductance similar to IA of molluscan neurons may serve to regulate the excitability of some central mammalian neurons. Depression of this conductance by 4-AP could contribute to the drug's convulsant effects in vivo.

Action Potentials↗
PubMed1983

Effects of 4-aminopyridine on calcium action potentials and calcium current under voltage clamp in spinal neurons.

We examined the effects of 4-aminopyridine (4-AP) on calcium conductance mechanisms in cultured mouse spinal cord neurons. At low concentrations (less than or equal to 1 mM), 4-AP enhanced Ca2+-dependent transmitter release and prolonged the duration of Ca2+-dependent action potentials. Voltage clamp studies indicated that 4-AP directly facilitates Ca2+ entry through voltage sensitive channels apart from an effect on K+ currents. These results may help to explain why the drug promotes Ca2+-dependent transmitter release at peripheral and central synapses.

4-Aminopyridine↗
PubMed1982

Activation of lateral geniculate neurons by locus coeruleus or dorsal noradrenergic bundle stimulation: selective blockade by the alpha 1-adrenoceptor antagonist prazosin.

Presentation of a stimulus train to the locus coeruleus (LC) or dorsal noradrenergic bundle (DB) resulted in a facilitation of the spontaneous firing of single units in the dorsal lateral geniculate nucleus (LGNd) of the rat. These stimulation effects were blocked by the alpha 1-adrenoceptor antagonists WB-4101 and prazosin. Both drugs also blocked the activation of LGNd neurons by iontophoretic norepinephrine (NE). The cholinergic agonists acetylcholine (ACh) and carbachol (CCh) activated LGNd neurons in a similar fashion to NE, however, these responses were selectively blocked by the muscarinic antagonist scopolamine. The response to ACh was also sensitive to WB-4101 suggesting that the drug possesses some cholinergic blocking activity. In contrast to WB-4101, prazosin displayed a high degree of selectivity for noradrenergic but not cholinergic responses. On the basis of the observation that prazosin selectively antagonizes both the stimulation effects and iontophoretic NE (but not CCh), we conclude that activation of LGNd neurons by LC or DB stimulation is mediated predominantly via the release of NE from coeruleo-geniculate fibers, rather than the inadvertent activation of a cholinergic pathway. Moreover, inasmuch as the systemic administration of prazosin effectively blocks central noradrenergic neurotransmission at doses comparable to those used clinically, the possibility that prazosin exerts its antihypertensive action in part via a central mechanism requires further investigation.

Action Potentials↗
PubMed1981

Serotonin autoreceptors on dorsal raphe neurons: structure-activity relationships of tryptamine analogs.

A series of indole-ethylamines were tested for their ability to suppress the spontaneous firing of single dorsal raphe serotonergic neurons in the rat. The compounds were all derivatives of either tryptamine or N,N-dimethyltryptamine possessing hydroxy or methoxy substituents on the benzene ring portion of the indole nucleus. Their activity was assessed using quantitative microiontophoresis or following systemic (intravenous) administration. The serotonin autoreceptor or so-called "S2 receptor" mediating the inhibition of raphe serotonergic neurons was found to exhibit a high degree of structural specificity among the closely related tryptamine analogs. The following structure-activity rules were demonstrated: (1) for either hydroxy or methoxy derivatives, the relative favorability of the ring positions conforms to the series 5 much greater than 4 greater than 6; (2) methoxy derivatives are more sensitive to a shift of the ring substituent from the 5- to the 4- or 6-positions than are hydroxy compounds; and (3) activity is enhanced by N,N-dimethylation. Furthermore, addition of a methyl group at the 7-position of 5-methoxy-N,N-dimethyltryptamine markedly reduces the activity of this potent agonist. Of the radioligands which label brain serotonin receptors, the pharmacological characteristics of D-[3H]lysergic acid diethylamide binding best correspond to those displayed by the S2 receptor as determined in the present physiological analysis, although sufficient data are not yet available to make a complete comparison.

Animals↗
PubMed1980

Modulation of lateral geniculate neurone excitability by noradrenaline microiontophoresis or locus coeruleus stimulation.

The dorsal lateral geniculate nucleus (LGNd) receives afferents from the brainstem which regulate its capacity to transmit visual information from the retina to the striate cortex. One such pathway consists of noradrenaline (NA)-containing fibres originating in the locus coeruleus (LC). These provide a dense, uniform, noradrenergic innervation of the LGNd. Electrical stimulation in the LC region has been reported to enhance the responsiveness of LGNd neurones to afferent excitation. Although this effect was abolished when brain NA stores were pharmacologically depleted, it was not established as a direct action of NA on LGNd neurones because of the widespread distribution of LC fibres to many parts of the brain and the long latency of the response. Recently, we observed that NA, applied locally by microiontophoresis with low ejection currents, produced a delayed increase in the firing rate of most spontaneously active LGNd neurones, an effect selectively blocked by alpha-adrenoceptor antagonists. We show here that microiontophoretic NA can mimic the ability of LC stimulation to enhance the synaptic excitation of LGNd neurones. As neither NA nor LC stimulation activated LGNd neurones in the absence of synaptic or glutamate-induced excitation, both appear to act through a neuromodulatory mechanism. The postsynaptic alpha-adrenoceptor antagonist WB-4101 blocks the facilitation produced by locally applied NA and by coeruleo-geniculate pathway stimulation, providing evidence for pharmacological identity of the two effects.

Action Potentials↗
PubMed1980

Activation of lateral geniculate neurons by norepinephrine: mediation by an alpha-adrenergic receptor.

Adrenergic receptors in the vicinity of neurons in the lateral geniculate nucleus (LGN) of the rat were pharmacologically characterized using extracellular single-cell recording and microiontophoretic techniques. Application of norepinephrine (NE) at low iontophoretic currents (1-15 nA) produced a delayed activation of most LGN neurons. This activation was mimicked by various sympathomimetic amines. The relative potency series of agonists was typical of postsynaptic alpha-adrenergic receptors: epinephrine greater than NE greater than phenylephrine greater than or equal to alpha-methylnorepinephrine greater than dopamine greater than isoproterenol. The alpha-antagonists phentolamine, piperoxane and WB-4101, when applied at low iontophoretic currents (less than 10 nA), produced a selective, dose-dependent and reversible blockade of the response to NE. The beta-antagonist sotalol had weak and variable effects at these currents. At low currents, the presynaptic alpha-agonist clonidine was also able to block the response to NE but, at higher currents, produced a partial activation of some units, suggesting that it is a weak agonist. The ability of sympathomimetic amines to activate LGN neurons correlates well with their reported affinities for brain alpha1-adrenoceptors labeled with [3H]WB-4101. It is concluded that NE activates neurons in the LGN via a postsynaptic or alpha1-adrenergic receptor.

Adrenergic alpha-Antagonists↗
PubMed1978

Hirschsprung's disease: absence of serotonergic neurons in the aganglionic colon.

The distribution of enteric serotonergic neurons was studied in patients with Hirschsprung's disease. Specimens of bowel obtained at surgery were incubated in vitro with tritiated serotonin (3H-5-HT) in the presence of a high concentration of nonradioactive norepinephrine. Sites of high-affinity 3H-5-HT uptake were visualized by light-microscopic autoradiography. Specimens taken from ganglionic regions of the intestine (distal ileum or colon) showed intense labeling of the neuropil within the myenteric plexus. Silver grains were localized in a pericellular distribution around ganglion cells, but the ganglion cells themselves were relatively free of overlying silver grains. Corresponding regions of aganglionic colon or rectum demonstrated silver grain densities equivalent to background levels. Specific labeling was absent over the large nerve trunks in this region. These results suggest that 5-HT-containing neurons are present in the normal human intestine and that these neurons are absent in the aganglionic segment in Hirshsprung's disease.

Autoradiography↗