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Biomedical subjects

M E Morris

Publications and source records attributed to M E Morris.

At least 127 records · Page 7Linked to original sources
PubMed1985

Changes in intracellular free Ca ion concentration evoked by electrical activity in cat spinal neurons in situ.

In cats under allobarbitone anaesthesia, Ca2+-sensitive microelectrodes were inserted into the lumbosacral spinal neurons to measure intracellular free Ca2+ concentration [Ca]i. In 72 resting motoneurons, the global mean [Ca]i was 7.9 microM (SD +/- 25.9). In the 36 "best" cells (with resting and action potentials better than 60 mV), mean [Ca]i was 1.6 microM (SD +/- 1.64). Activation of motoneurons by antidromic or direct stimulation evoked mean increases in [Ca]i of about 90 nM when stimulating for 30 s at 10 Hz, and 170 nM at 20 Hz. The mean time to half-recovery was 23 s (SD +/- 14.5). Orthodromic stimulation consistently produced smaller increases in [Ca]i. Measurements in motor axons showed a comparable resting level of [Ca]i, but only minimal changes during stimulation, even at 100 Hz. Sensory axons (also recorded within the spinal cord) similarly failed to show any increase in [Ca]i during high frequency stimulation. In some interneurons, however, particularly large and rapid increases in [Ca]i could be evoked by dorsal root stimulation at 1-5 Hz. Unresponsive cells (presumably neuroglia), with a typically high and stable resting potential, had a variable [Ca]i giving a mean of 32 microM (SD +/- 63.0). A tentative theoretical analysis of the magnitude and time course of delta [Ca]i evoked in motoneurons by tetanic stimulation is consistent with remarkably slow apparent diffusion of intracellular Ca2+ (1/250 of rate of diffusion in water), such as might be expected in the presence of very efficient mechanisms of Ca2+ sequestration.

Animals↗
PubMed1985

Antagonist actions of bicuculline methiodide and picrotoxin on extrasynaptic gamma-aminobutyric acid receptors.

The effects of picrotoxin and bicuculline methiodide to block depolarizing responses of extrasynaptic receptors for gamma-aminobutyric acid (GABA) are compared using excitability testing of myelinated axons in amphibian peripheral nerve. The actions of the antagonists appear both complex and dissimilar. Picrotoxin (10-1000 microM) produces large reversible depressions of the maximal response to GABA (0.01-10mM) and increases the EC50 from 0.33 to 12.6 mM. With high concentrations of agonist and antagonist an insensitive component is apparent. The action of picrotoxin is not classically noncompetitive: it may represent a mixed antagonism (competitive and noncompetitive) or a noncompetitive one, masked by the presence of receptor reserve and (or) secondary depolarizing influences (e.g., GABA-evoked [K+] o accumulation). Bicuculline methiodide (10-200 microM) shifts the GABA concentration-response curve to the right; maximal responses persist and are even enhanced. The impression that bicuculline methiodide has a competitive action is supported by analysis of its inhibition of responses to low concentrations of the agonist. It is suggested that the enhancement of GABA responses by bicuculline methiodide and their apparent resistance to block by picrotoxin may be due to a common secondary effect of the antagonists such as a decrease in membrane conductance to K+ and (or) block of transmitter uptake.

Animals↗
PubMed1984

Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans.

The renal clearances of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were determined in eight healthy adults 2 h after administration of 1.5 g of acetaminophen. The renal clearance ratios (relative to creatinine) were 0.058 +/- 0.026, 0.890 +/- 0.153, and 1.43 +/- 0.250 (mean +/- SD), respectively. The renal clearance of acetaminophen increased with increasing urine flow rate, and that of acetaminophen sulfate decreased with increasing serum concentration of the conjugate. A strong positive correlation was found between the renal clearances of acetaminophen glucuronide and acetaminophen sulfate, possibly due to blood perfusion rate-dependent renal tubular secretion of the two conjugates. The serum protein binding of acetaminophen (congruent to 20%) and acetaminophen glucuronide (less than 10%) are minor. Acetaminophen sulfate is greater than 50% protein bound, as determined by equilibrium dialysis and ultrafiltration. The results of these studies are (a) consistent with previous reports of animal studies, indicating that renal excretion of acetaminophen involves glomerular filtration and passive reabsorption and that acetaminophen sulfate is subject to active renal tubular secretion, and (b) compatible with the reported occurrence of renal tubular secretion of acetaminophen glucuronide in animals.

Acetaminophen↗
PubMed1984

Lathyrus excitotoxin: mechanism of neuronal excitation by L-2-oxalylamino-3-amino- and L-3-oxalylamino-2-amino-propionic acid.

Intracellular recordings were made in cultured neurones from foetal mouse spinal cord. The effects of applications of the neurotoxin, L-3-oxalylamino-2-amino-propionic acid (a constituent of the chickling pea, Lathyrus sativus) and its 2-oxalylamino isomer on membrane potential and conductance were examined in the presence of TTX and TEA and compared to those of other excitatory amino acids. Although both compounds produced membrane depolarization and an increase in input conductance, the 3-oxalylamino isomer (beta-ODAP) was approximately equal to 10 times more potent than the 2-oxalylamino isomer (alpha-ODAP). beta-ODAP caused a voltage-independent change in conductance, as compared to an apparent voltage-dependent decrease produced in the same neurons by L-aspartic acid (L-ASP). Although reversal potentials determined for beta-ODAP resembled those for alpha-ODAP and kainic acid, they were consistently and significantly lower than the reversal level for L-ASP. Although the receptor antagonist 2-amino-5-phosphonovaleric acid (APV) and the divalent cation Cd2+ did not alter the conductance increase evoked by beta-ODAP, they markedly depressed responses to L-ASP. Such differences suggest a mechanism of excitatory action for the neurotoxin, beta-ODAP, which does not involve a Ca2+-dependent mechanism and is quite different from that for L-ASP and N-methyl-D-aspartic acid, but similar to that of kainic and quisqualic acids.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1983

Depolarizing action of GABA (gamma-aminobutyric acid) on myelinated fibers of peripheral nerves.

The inhibitory neurotransmitter GABA (gamma-aminobutyric acid) has been shown to have a depolarizing action on myelinated axons of both mammalian and amphibian peripheral nerves. In initial in vivo observations intravenous injections of GABA caused an increase in the excitability of the low-threshold, fast conducting fibers of the superficial radial and median nerves of the cat. Similar, graded, reversible effects were confirmed (using changes in the amplitude/integral of the stimulus-evoked A-fiber submaximal compound action potential to assess excitability) in in vitro studies with the isolated, desheathed frog sciatic nerve. GABA caused a mean maximal increase in half-maximal action potential of 29.8% (S.E. +/- 2.7), with an ED50 value of 0.09 mM and Hill coefficient of 0.70. This effect did not appear to desensitize, and could be reversibly antagonized by both bicuculline and picrotoxin. Comparison of agonist sensitivities showed a rank order of potency with muscimol greater than 3-aminopropanesulfonic acid greater than GABA greater than beta-guanidinopropionic acid greater than imidazole-acetic acid greater than guanidoacetic acid greater than delta-aminovaleric acid. With structure activity analysis the maximal activity was found to be related to N+-C separation near the 5 A value. Partial substitution of chloride ions in the superfusate by isethionate reversibly depressed the effect of GABA. These observations support the conclusion that extrasynaptic receptors for GABA are present on the myelinated axons of peripheral nerves.

Animals↗
PubMed1983

Role of K+ in GABA (gamma-aminobutyric acid)-evoked depolarization of peripheral nerve.

Isolated, desheathed sciatic nerves of the leopard frog or bull frog were used in studies to determine different sources/components of the depolarizing effect of GABA (gamma-aminobutyric acid) on myelinated fibers. During the depolarization induced by 1 mM GABA--which was reflected by an increase of 38.3% (S.E. +/- 2.2) in the amplitude of the evoked half-maximal A-fiber compound action potential--the level of extracellular potassium ([K+]o) measured at depths less than or equal to 200 microns in the nerve with ion-selective microelectrodes, increased by 0.096 mM (S.E. +/- 0.007). Changes in excitability preceded K+]o, and there was a significant difference between their peak latencies. Artificially raised levels of [K+]o, similar to those induced by GABA, caused extremely small changes (less than 10%) in the size of the evoked action potential. From the magnitude and time course of the GABA-evoked augmentation of levels of [K+]o, it can be concluded that potassium ions probably arise indirectly and play a secondary role in what appears to be a mainly receptor-mediated depolarization of axons. A much greater sensitivity to GABA was found for fibers of the dorsal roots in comparison with those of the ventral roots (maximal changes in excitability of 50% and 6% respectively). This suggests that the depolarization of ventral root fibers could be caused by [K+]o accumulation, and that there may be a preferentially localized distribution of receptors for GABA on the sensory axons of peripheral nerve.

Animals↗
PubMed1983

Determination of salicylamide and five metabolites in biological fluids by high-performance liquid chromatography.

Two high-performance liquid chromatographic (HPLC) assay procedures were developed for the determination of salicylamide and its metabolites in serum, urine, and saliva. One method involves reverse-phase ion-pair chromatography and UV detection, and is used to determine salicylamide, salicylamide glucuronide, and salicylamide sulfate. The other method, with a different mobile phase and without the ion-pairing reagent, is used to determine gentisamide (the hydroxylated metabolite of salicylamide), gentisamide glucuronide, and gentisamide sulfate. The assays are performed by direct injection of the sample after protein precipitation with ethanol containing the internal standard. Increased sensitivity for the determination of low concentrations of salicylamide is obtained by organic extraction of this drug from serum or saliva. Calibration curves for the conjugates of salicylamide and gentisamide were obtained, in the absence of authentic standards, by partial enzymatic hydrolysis, using the decrease of the conjugate peaks and the concomitant increase of free salicylamide or gentisamide concentrations to determine peak area ratio-concentration relationships. Application of the HPLC assay procedures to the determination of salicylamide excretion products in the urine of three normal human subjects resulted in 98.6% (range:97.1-100.1%) recovery of a 1-g oral dose of the drug. All five metabolites of salicylamide were found in urine, but only salicylamide glucuronide, salicylamide sulfate, and gentisamide glucuronide were found consistently and in appreciable quantities. Salicylamide and all of its metabolites except gentisamide sulfate were found in human and rat serum, and unconjugated salicylamide as well as gentisamide were found in human saliva.

Animals↗
PubMed1983

Serum concentration and renal excretion by normal adults of inorganic sulfate after acetaminophen, ascorbic acid, or sodium sulfate.

Depletion of endogenous inorganic sulfate can have pronounced effects on the elimination kinetics and metabolic fate of phenolic drugs. Our purpose was to determine the effects of acetaminophen (which is partly metabolized to acetaminophen sulfate), ascorbic acid (subject to more limited sulfation than acetaminophen), and sodium sulfate (useful for sulfate repletion by the oral route) on the serum concentration and renal excretion of inorganic sulfate in healthy adults. Six men and two women, 26 to 35 yr old, were studied on four occasions that were at least 4 days apart. They received no medication, 1.5 gm acetaminophen, 6 gm ascorbic acid, or 9 gm sodium sulfate decahydrate orally, in aqueous solution. A blood sample was obtained 2 hr later and urine was collected from 1 to 3 hr. Serum inorganic sulfate concentrations (mean +/- SD), 0.410 +/- 0.043 mM in the control period, were decreased after acetaminophen (0.311 +/- 0.043 mM, P less than 0.001), increased after sodium sulfate (0.513 +/- 0.055 mM, P less than 0.001), and apparently unchanged after ascorbic acid (0.417 +/- 0.059 mM). The urinary excretion of inorganic sulfate was decreased after acetaminophen and increased after sodium sulfate. The renal clearance of endogenous creatinine was not affected by any of the treatments. The renal tubular reabsorption of inorganic sulfate is capacity limited, as evidenced by the decrease of the reabsorbed fraction with increasing glomerular filtration rate of the anion (r = -0.54, P less than 0.005). This saturable reabsorption facilitates sulfate homeostasis.

Acetaminophen↗
PubMed1983

Absorption of sulfate from orally administered magnesium sulfate in man.

The purpose of this investigation was to determine the suitability of orally administered magnesium sulfate as a source of inorganic sulfate for counteracting the systemic depletion of sulfate caused by large doses of acetaminophen and certain other drugs that are metabolized to sulfate conjugates. Oral administration of 13.9 g magnesium sulfate U.S.P., in 4 equal hourly increments, to seven healthy men resulted in the urinary excretion (corrected for baseline excretion rate) of an amount of inorganic sulfate equivalent to 30.2 +/- 17.2 percent (mean +/- SD) of the dose during the first 24 hours. Excretion during the subsequent 48 hours was negligible. Six of the subjects experienced loose stools or diarrhea. Compared to sodium sulfate, magnesium sulfate appears to be absorbed less completely and more erratically, and to produce more adverse effects.

Administration, Oral↗
PubMed1982

Stimulation-evoked changes in extracellular K+ and Ca2+ in pyramidal layers of the rat's hippocampus.

In urethane-anaesthetized rats, ion-selective microelectrodes recorded changes in extracellular K+ and Ca2+ concentrations (delta[K+]omicron and delta[Ca2+]omicron) in pyramidal layers of the hippocampus (mostly in area CA1), which were evoked by fimbrial-commissural stimulation. [K+]omicron increased linearly with frequency of stimulation up to a critical frequency, in the range of 2-5 Hz, where bursts of population spikes appeared, and then rose rapidly to reach a ceiling of 9-12 mM. During continued stimulation, [K+]omicron remained well above the resting level of about 3.0 mM. At the end of stimulation [K+]omicron returned to the base line with a half time of 4-8 s, and a minor undershoot of congruent to 0.5 mM was detectable for 1-2 min. When stimulating at frequencies above the critical value, a sharp fall in [Ca2+]omicron (by an average of one-third below the mean resting level of 1.4 mM) consistently started 1-5 s after the onset of the rapid phase of delta[K+]omicron. [Ca2+]omicron typically reached a minimum in 5-10 s and immediately started to return towards the base line. The recovery of [Ca2+]omicron was often accelerated by an overshoot of up to 0.3 mM; this was followed by a delayed phase of low [Ca2+]omicron for another 2-3 min. During prolonged stimulation at frequencies near 7 Hz, both [Ca2+]omicron and [K+]omicron fluctuated periodically, in time with the appearance and disappearance of bursts of population spikes. Comparable observations were made in area CA2-3 (just external to CA1); in the deeper areas of CA3, in CA4, and in the dentate gyrus, major changes in [K+]omicron and [Ca2+]omicron (as well as bursts of population spikes) were evoked only by prolonged fimbrial stimulation at higher frequencies (congruent to 10 Hz). Thus, although adequate repetitive stimulation of fimbrial-commissural inputs evokes sharp but opposite changes in [K+]omicron and [Ca2+]omicron, the fall in [Ca2+]omicron is consistently much briefer than the rise in [K+]omicron, presumably because of the evanescent character of postsynaptic Ca2+ spikes.

Animals↗
PubMed1982

Depth distribution and mechanism of changes in extracellular K+ and Ca2+ concentrations in the hippocampus.

In the CA1 area of the hippocampus of urethane-anaesthetized rats, the greatest delta[K+]omicron and delta[Ca2+]omicron evoked by repetitive fimbrial-commissural stimulation were always found in the pyramidal cell layer; but there were large increases in [K+]omicron over a wide range of depth, whereas a major fall in [Ca2+]omicron was localized almost exclusively to the level of the pyramidal layer. A sustained focal negative potential was also evoked by fimbrial stimulation; it resembled delta[K+]omicron in time course and depth distribution and therefore probably reflected cellular depolarization caused by increased [K+]omicron. The close correlation between delta[Ca2+]omicron and delta[K+]omicron and the appearance of population spikes (especially in bursts of three to four spikes) indicate that pyramidal cell firing and corresponding K-outward and Ca-inward currents are mainly responsible for the accumulation of K+omicron and the depletion of Ca2+omicron. In CA3 pyramidal areas, delta [K+]omicron and delta[Ca2+]omicron were comparable in magnitude and distribution to changes seen in CA1, but they occurred after a longer latency, and the major delta[Ca2+]omicron had a longer duration, consistent with a more prolonged Ca2+ current.

Animals↗
PubMed1981

Slow diffusion of Ca2+ in the rat's hippocampus.

Ca2+-sensitive microelectrodes, attached to CaCl2-containing micropipettes, were inserted into the dorsal hippocampus of rats under urethane. When Ca2+ was released iontophoretically, the amplitude and time course of the resultant increase in extracellular ca2+ concentration could be fitted to a simple diffusion model, but the apparent diffusion coefficient of Ca2+ was only about 1/100 of its value in water, possibly because of reversible Ca/+ binding to hippocampal tissue. A further anomaly was a very low transport number (less than 0.01) for the release of Ca2+ from microelectrodes in vivo.

Animals↗
PubMed1980

Changes in extracellular Ca2+ and K+ activity accompanying hippocampal discharges.

In rats under urethane anaesthesia, changes in the extracellular activities of K+ and Ca2+ (alpha K and alpha Ca) evoked by fimbrial or entorhinal stimulation and recorded in area CA3 with ion-selective microelectrodes are maximal in the pyramidal cell layers. With 10/s stimulation, alpha K increases by 6--9 mM whereas alpha Ca falls by 0.5--1.0 mM. In contrast with the increase in alpha K, which is distributed over a wide range of depth, the reduction in alpha Ca is particularly sharply limited to the level of pyramidal cell bodies. It is regularly associated with a negative aferpotential in the extracellular field, which presumably reflects a large postsynaptic Ca2+ inward current, apparently predominant in the cell bodies. Repetitive stimulation sometimes evokes spreading depressionlike swings in potential, which are seen only near the pyramidal stratum and are accompanied by massive increases in alpha K (to 30--40 mM) and falls in alpha Ca (to < 0.1 mM). A large Ca2+ influx into pyramidal cells may be of significance for "plastic" aspects of hippocampal function and when excessive, as during repetitive convulsive activity, may be responsible for the necrosis of CA3 neurons.

Animals↗