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Biomedical subjects

B E Slack

Publications and source records attributed to B E Slack.

28 records · Page 2Linked to original sources
PubMed1991

Alterations of phospholipid metabolites in postmortem brain from patients with Alzheimer's disease.

To test the hypothesis that brain cell membranes degenerate in Alzheimer's disease (AD), we measured the levels of phospholipids, their water-soluble metabolites, and glycerophosphocholine (GPC) cholinephosphodiesterase activity in postmortem brain tissue from patients with AD and age-matched controls. We found significantly higher levels of the phospholipid catabolite GPC in AD brain. In contrast, choline and ethanolamine levels were significantly lower in AD, and phospholipid levels were slightly decreased. Furthermore, in AD the activity of the GPC-degrading enzyme GPC cholinephosphodiesterase was unaltered. Our results indicate that membrane phospholipid catabolism is increased in AD brain. Inasmuch as the tissue levels of initial phospholipid precursors were decreased, we suggest that phospholipid turnover is elevated in this neurodegenerative disease.

Alzheimer Disease↗
PubMed1989

Uptake of exogenous phosphatidylserine by human neuroblastoma cells stimulates the incorporation of [methyl-14C]choline into phosphatidylcholine.

The phosphatidylserine (PtdSer) content of human cholinergic neuroblastoma (LA-N-2) cells was manipulated by exposing the cells to exogenous PtdSer, and the effects on phospholipid content, membrane composition, and incorporation of choline into phosphatidylcholine (PtdCho) were investigated. The presence of liposomes containing PtdSer (10-130 microM) in the medium caused time- and concentration-dependent increases in the PtdSer content of the cells, and smaller and slower increases in the contents of other membrane phospholipids. The PtdSer levels in plasma membrane and mitochondrial fractions prepared by discontinuous sucrose density gradient centrifugation increased by 50 and 100%, respectively, above those in control cells after 24 h of exposure to PtdSer (130 microM). PtdSer caused a concomitant, concentration-dependent increase of up to twofold in the incorporation of [methyl-14C]choline chloride into PtdCho at a choline concentration (8.5 microM) compatible with activation of the CDP-choline pathway, suggesting that the levels of PtdSer in membranes may serve as a stimulus to regulate overall membrane composition. PtdSer caused a mean increase of 41% in PtdCho labeling, but the phorbol ester, phorbol 12-myristate 13-acetate (PMA), which stimulates PtdCho synthesis in a number of cell lines, increased [14C]PtdCho levels by only 14% in LA-N-2 cells, at a concentration (100 nM) which caused complete translocation of the calcium- and phospholipid-dependent enzyme protein kinase C to the membrane. The translocation was inhibited by prior exposure of the cells to PtdSer. Treatment with PMA for 24 h diminished protein kinase C activity by 80%, but increased the labeling of PtdCho in both untreated and PtdSer-treated cells. These data suggest that uptake of PtdSer by LA-N-2 cells alters both the phospholipid composition of the membrane and synthesis of the major membrane phospholipid PtdCho; the latter effect does not involve activation of protein kinase C.

Biological Transport↗
PubMed1986

Pre- and postsynaptic actions of noradrenaline and clonidine on myenteric neurons.

alpha-2 adrenergic agonists inhibit nicotinic excitatory postsynaptic potentials and reduce calcium dependent action potentials in myenteric neurons. To test the hypothesis that adrenergic inhibitory effects on action potential configuration and on inhibition of acetylcholine release from the nerve terminal are analogous processes, the pharmacological characteristics and underlying mechanisms of these two effects were compared in neurons of the myenteric plexus in the guinea pig. Both clonidine and noradrenaline reduced the nicotinic fast excitatory postsynaptic potential in a concentration dependent manner, although the maximum effect produced by noradrenaline was greater. The specific alpha-2 antagonist RX781094 blocked the action of noradrenaline, with an apparent Kd value of 3.8 +/- 1 nM. Clonidine was similarly antagonized by low concentrations of this compound. The potassium channel blocker barium prevented inhibition of the fast excitatory postsynaptic potential by clonidine but not by noradrenaline. Action potentials recorded from after-hyperpolarization neurons with cesium chloride filled electrodes were prolonged in duration due to the blockade by cesium of outward potassium movement. Under these conditions, noradrenaline reduced action potential duration and slowed the rate of rise of the calcium dependent component in the presence of tetrodotoxin. RX781094 antagonized the latter effect with an estimated apparent Kd of 5.8 +/- nM. The rate of rise of the calcium dependent action potential was not affected by clonidine (30 nM to 1 microM). In the absence of potassium channel blockers noradrenaline caused hyperpolarizations which were blocked by RX781094. It has been previously shown that clonidine hyperpolarizes myenteric neurons via an adrenergically mediated increase in potassium conductance. It was concluded that the characteristics of presynaptic inhibition of release by noradrenaline and clonidine parallel the respective actions of these agonists on action potential configuration. While all clonidine effects could be explained on the basis of an increase in potassium conductance, noradrenaline exerted an additional inhibitory action which persisted in the presence of potassium channel blockade by barium or cesium.

Action Potentials↗
PubMed1986

Inositol-1,4,5-trisphosphate injection mimics fertilization potentials in sea urchin eggs.

The effects of inositol-1,4,5-trisphosphate (IP3) and of diacylglycerol (DAG) and its analogues on the membrane potential of eggs from the sea urchin Strongylocentrotus purpuratus were examined. Injection of IP3 into eggs resulted in a change in membrane potential that was similar in magnitude and time course to the fertilization potential elicited by sperm attachment. In low-calcium seawater, IP3 injection elicited a partial response. DAG and its analogues phorbol myristyl acetate and 1-oleoyl-2-acetylglycerol did not affect membrane potential either when applied by perfusion or when injected. The results indicate that IP3, but not DAG or its analogues, may be involved in the generation of the fertilization potential triggered by the interaction of sperm with sea urchin eggs.

Animals↗
PubMed1985

Muscarinic M1 and M2 receptors mediate depolarization and presynaptic inhibition in guinea-pig enteric nervous system.

Intracellular recordings were made from guinea-pig myenteric and submucous plexus neurones. Nicotinic excitatory post-synaptic potentials (fast e.p.s.p.s) and slow e.p.s.p.s were recorded in both plexuses; adrenergic inhibitory post-synaptic potentials (i.p.s.p.s) were recorded from submucous plexus neurones. The effects of muscarinic agonists and antagonists were examined on the synaptic potentials in those neurones in which these substances did not change the membrane potential. Muscarine, oxotremorine, methylfurmethide and McNeil A343 reversibly depressed the amplitude of the fast e.p.s.p. in a concentration-dependent way. Hyoscine, pirenzepine and 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) caused a parallel shift to the right of the agonist dose-response curves. These muscarinic antagonists themselves did not alter the amplitudes of fast e.p.s.p.s evoked by low frequency (0.05-0.1 Hz) stimulation. Antagonist pA2 values (the negative logarithm of the dissociation equilibrium constant) were determined while recording from individual neurones. pA2 values were: pirenzepine 7.0, hyoscine 8.9, and 4-DAMP 8.7. I.p.s.p.s in the submucous plexus were also depressed by muscarinic agonists, and this was competitively reversed by pirenzepine and 4-DAMP, with apparent pA2 values of 6.9 and 8.7 respectively. Muscarinic antagonists alone increased the amplitude of the i.p.s.p. evoked either by single or repeated stimuli. This enhancement was observed with low concentrations of antagonists and did not become greater when the concentrations were increased. Muscarinic agonists depolarized about one-quarter of myenteric and submucous plexus neurones. Low concentrations of pirenzepine antagonized these depolarizations; the pA2 value was 8.4. Cholinergic slow e.p.s.p.s recorded in some myenteric neurones were depressed or abolished by pirenzepine; concentrations that caused 50% inhibition (IC50) for this action ranged from 10 to 60 nM. It is concluded that presynaptic muscarinic receptors, activation of which inhibits the release of acetylcholine and noradrenaline, are the m2 type. Post-synaptic muscarinic receptors, activation of which depolarizes the membrane, are of the m1 type. The results also suggest that acetylcholine may exert a tonic inhibition of noradrenaline release in the submucous plexus through m2 receptors, and mediates the slow e.p.s.p. in the myenteric plexus through m1 receptors.

Action Potentials↗
PubMed1983

Pharmacological analysis of the responses of the feline urethra to autonomic nerve stimulation.

The effects of sympathetic and parasympathetic nerve stimulation on resistance to flow in the proximal urethra was examined in male, chloralose-anesthetized cats. Hypogastric (sympathetic) nerve stimulation increased urethral resistance, an effect that was blocked by the alpha-adrenergic antagonist prazosin (0.1 mg/kg), reduced 50% by ganglionic blockade with hexamethonium (0.4 to 0.6 mg/min) and potentiated by the beta-adrenergic antagonist sotalol (5 mg/kg). In the presence of phenylephrine-induced constrictions of the urethra, hypogastric nerve stimulation decreased resistance by a sotalol-sensitive, hexamethonium-resistant mechanism. The results imply that sympathetic stimulation can either raise or lower urethral resistance under different conditions, and that the organization of the nerves mediating the two types of response differs. Because pelvic nerve stimulation produced small and inconsistent responses, the parasympathetic input was instead activated by sacral ventral root stimulation. Sacral stimulation produced an atropine-sensitive constriction when basal urethral resistance was low, and dilatation when resistance was high. The latter response was reduced by atropine, but was resistant to sotalol. However, the decrease in resistance produced by acetylcholine in the presence of PE was not reduced by atropine, implying that acetylcholine-induced dilatation of the urethra is not due to activation of muscarinic receptors on smooth muscle. It is hypothesized that parasympathetic dilatation of the urethra may be mediated by a non-cholinergic, non-adrenergic inhibitory transmitter released from post-ganglionic neurons. A muscarinic mechanism may be involved in this response either to potentiate the action of the unknown transmitter or to facilitate the ganglionic excitation of these neurons. Parasympathetic constrictor responses can be attributed to activation of postganglionic cholinergic neurons.

Acetylcholine↗
PubMed1983

Sensitivity to indomethacin of tetrodotoxin-resistant contractions of smooth muscle from the base of rabbit bladder.

Tetrodotoxin (TTX) reduced the contractions to field stimulation of strips of rabbit bladder base by 58% of control (at 40 Hz), and increased the spontaneous activity occurring between the evoked responses. The TTX-resistant contractions resembled the spontaneous activity in that they were of comparable size and poorly sustained; in the presence of indomethacin, TTX produced a significantly greater reduction (to 13% of control at 40 Hz), of the evoked contractions. Indomethacin abolished spontaneous activity in the presence and absence of TTX, but did not affect evoked responses in strips that were not exposed to TTX. The results imply that a prostaglandin-like substance may potentiate residual evoked responses in TTX-treated strips, but does not contribute to field stimulation-induced contractions in untreated bladder base smooth muscle.

Animals↗
PubMed1982

Paradoxical resistance to adrenolytic agents of field-stimulated bladder base of rabbit.

Isolated circulatory or longitudinally oriented strips from anterior or posterior rabbit bladder base were tested for responsiveness to agonists and sensitivity of field stimulation-induced responses to antagonists. Results were compared to the regional distribution of adrenergic and cholinergic nerves determined histochemically. Greater norepinephrine-induced responses in posterior than in anterior strips reflect denser noradrenergic innervation in posterior base. Longitudinal strips responded better to carbachol than circular strips, but no orientation-related differences in cholinergic nerve density or muscle mass were noted. Field stimulation-induced contractions were largely resistant to phenoxybenzamine (0.03 microM) and guanethidine (100 microM) and slightly reduced by phentolamine (2.6 microM). Atropine (0.4 microM) reduced maximum responses by 25 to 75%. The resistance to guanethidine suggests that the ineffectiveness of phenoxybenzamine is not due solely to atypical post synaptic receptors. Inaccessibility of the synaptic cleft to guanethidine is unlikely because the vas deferens, which possesses close contacts, was sensitive to guanethidine. Neurotransmission in bladder base may be partially noradrenergic, noncholinergic in nature. A question arises concerning the functional significance of the noradrenergic nerves in bladder base.

Animals↗