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PubMed1993

Characterization of muscarinic receptors in cultured human iris sphincter and ciliary smooth muscle cells.

Muscarinic receptors present in cultured human iris sphincter and ciliary smooth muscle cells were characterized by both ligand ([3H]QNB binding) and functional (phosphoinositide hydrolysis) studies. Ligand binding studies showed that [3H]QNB represented a single population of binding sites with KD values of 4.02 x 10(-11) M in the ciliary and 5.6 x 10(-11) M in the iris sphincter cells. In competition studies, the selective antagonist, 4-diphenylacetoxy-N-methylpiperidine-methobromide (4-DAMP) was the most potent in displacing [3H]QNB with selectivity of 150-350-fold over pirenzepine (M1) and 450-1700-fold over AF-DX 116 (M2). 4-DAMP recognized one site in the iris sphincter cells (Ki = 0.34 nM) but two sites in the ciliary cells (KH = 0.9 nM and KL = 49 nM). 4-DAMP was also the most potent in inhibiting carbachol-induced hydrolysis of inositol phospholipids (PI) in both cell types. However, the IC50 values for PI hydrolysis were several fold lower than those for [3H]QNB binding. Using these selective antagonists, our data supports the presence of functional muscarinic receptors of M3 subtype in human iris sphincter and ciliary cells. It also shows the presence of a second low affinity site in the ciliary smooth muscle cells that is recognized by 4-DAMP.

Binding, Competitive↗

PubMed1991

Muscarinic responses of gastric parietal cells.

Isolated rabbit gastric glands were used to study the nature of the muscarinic cholinergic responses of parietal cells. Carbachol (CCh, 100 microM) stimulation of acid secretion, as measured by the accumulation of aminopyrine, was inhibited by the M1 antagonist, pirenzepine, with an IC50 of 13 microM; by the M2 antagonist, 11,2-(diethylamino)methyl-1 piperidinyl acetyl-5,11-dihydro-6H-pyrido 2,3-b 1,4 benzodiazepin-6-one (AF-DX 116), with an IC50 of 110 microM; and by the M1/M3 antagonist, diphenyl-acetoxy-4-methylpiperidinemethiodide (4-DAMP), with an IC50 of 35 nM. The three antagonists displayed equivalent IC50 values for the inhibition of carbachol-stimulated production of 14CO2 from radiolabeled glucose, which is a measure of the turnover of the H,K-ATPase, the final step of acid secretion. Intracellular calcium levels were measured in gastric glands loaded with FURA 2. Carbachol was shown to both release calcium from an intracellular pool and to promote calcium entry across the plasma membrane. The calcium entry was inhibitable by 20 microM La3+. The relative potency of the three muscarinic antagonists for inhibition of calcium entry was essentially the same as for inhibition of acid secretion or pump related glucose oxidation. Image analysis of the glands showed the effects of carbachol, and of the antagonists, on intracellular calcium were occurring largely in the parietal cell. The rise in cell calcium due to release of calcium from intracellular stores was inhibited by 4-DAMP with an IC50 of 1.7 nM, suggesting that the release pathway was regulated by a low affinity M3 muscarinic receptor or state; Ca entry and acid secretion are regulated by a high affinity M3 muscarinic receptor or state, inhibited by higher 4-DAMP concentrations (greater than 30 nM), suggesting that it is the steady-state elevation of Ca that is related to parietal cell function rather than the [Ca]i transient. Displacement of 3H N-methyl scopolamine (NMS) binding to purified parietal cells by CCh showed the presence of two affinities for CCh, but only a single affinity for 4-DAMP and lower affinity for pirenzepine and AFDX 116, providing further evidence for the parietal cell location of the [Ca]i response. Elevation of steady-state [Ca]i levels with either ionomycin or arachidonic acid did not replicate M3 stimulation of acid secretion or glucose oxidation, hence elevation of [Ca]i is necessary but not sufficient for acid secretion.

Aminopyrine↗

PubMed1996

Equivalence of fast flush and square wave testing of blood pressure monitoring systems.

BACKGROUND: The accurate recording of intraarterial pressure depends upon an appropriate dynamic response of the monitoring system. Generation of a square wave (SW) at the catheter tip is the engineering and in vitro laboratory gold standard. Fast flush (FF) testing is the clinical test of choice. Results from these two test methods have been assumed equal but have not been empirically confirmed. METHODS: We studied three different 5.1 cm catheter sizes (16 G, 18 G, 20 G Becton Dickinson, Sandy, UT) attached to three different lengths of arterial pressure tubing (36 in, 91.4 cm; 72 in, 182.9 cm; 108 in, 274.3 cm). An arterial recording system was assembled in the standard fashion by attaching a catheter to arterial pressure tubing, which was attached to a transducer (TXX-R, Ohmeda, formerly Viggo-Spectramed, Oxnard, CA) whose signal was recorded by a strip chart recorder (Gould 2400, Rolling Meadows, IL). The system was attached to a pressurized saline flush. The catheter tip was inserted into one port of a pressure generator. With the other port of the pressure generator open to atmosphere, FF tests were performed by activating the flush device of the transducer. Subsequent step response signals from the FF tests were then recorded from which natural frequency (fn) and damping coefficient (zeta) were calculated. Next, square waves were generated by closing the port that was open to atmosphere and attaching a signal generator to a pressure generator. Square waves so generated were recorded as described above and natural frequency and damping coefficients calculated. These procedures were repeated after 0.05 cc of air was introduced in the transducer and repeated again in a system containing a damping device (R.O.S.E., Resonant OverShoot Eliminator, Viggo-Spectramed, Oxnard, CA). RESULTS: There was no significant difference between fn and zeta as calculated from the step response generated from the FF test versus fn and zeta as calculated from the square wave (SW) test in systems without air. However, in systems containing air, fn by FF testing was always less than fn by SW testing for all catheter sizes and extension tubing lengths (p < 0.05). Damping was also always greater by FF testing than by SW testing in systems with air for all catheter sizes and extension tubing lengths (p < 0.05). The R.O.S.E device created marked qualitative differences, although exact fn and zeta could not be quantified. CONCLUSIONS: For the characterization of dynamic response of invasive blood pressure monitoring systems, the FF test and SW test yield identical results. However, under certain conditions-air, R.O.S.E device-dynamic response as measured by FF testing was not equivalent to dynamic response as measured by the gold standard-the SW test. Specifically, small amounts of air in fluid-filled invasive blood pressure monitoring systems cause a slightly worse dynamic response as measured by FF testing versus the laboratory gold standard-the SW test.

Blood Pressure Monitors↗

PubMed1998

Contractile and phosphatidylinositol responses of rat trachea to anticholinesterase drugs.

PURPOSE: Some anticholinesterases (anti-ChE) such as neostigmine and pyridostigmine but not edrophonium, stimulate phosphatidylinositol (PI) response. Although a direct relationship was suggested between the increase in PI response and airway smooth muscle contraction, there are no data regarding the effects of anti-ChE drugs on airway smooth muscle. Thus, we examined the contractile properties and PI responses produced by anti-ChE drugs. METHODS: Contractile response. Rat tracheal ring was suspended between two stainless hooks in Krebs-Henseleit (K-H) solution. (1) Carbachol (CCh), anti-ChE drugs (neostigmine, pyridostigmine, edrophonium) or DMPP (a selective ganglionic nicotinic agonist) were added to induce active contraction. (2) The effects of 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), an M3 muscarinic receptor antagonist, on neostigmine- or pyridostigmine-induced contraction of rat tracheal ring were examined. (3) Tetrodotoxin (TTX) was tested on the anti-ChE drugs-induced responses. PI response. The tracheal slices were incubated in K-H solution containing LiCl and 3[H]myo-inositol in the presence of neostigmine or pyridostigmine with or without 4-DAMP, an M3 muscarinic receptor antagonist. 3[H]inositol monophosphate (IP1) formed was counted with a liquid scintillation counter. RESULTS: Carbachol (0.1 microM), neostigmine (1 microM), pyridostigmine (10 microM) but not edrophonium or DMPP, caused tracheal ring contraction. 4-DAMP, but not tetrodotoxin, inhibited neostigmine and pyridostigmine-induced contraction. Neostigmine- or pyridostigmine-induced IP1, accumulation was inhibited by 4-DAMP. CONCLUSIONS: The data suggest that anti-ChE drugs activate the M3 receptors at the tracheal effector site.

Animals↗

PubMed2003

Brain muscarinic receptor subtypes mediating water intake and Fos following cerebroventricular administration of bethanecol in rats.

RATIONALE: The brain regions and receptor subtypes involved in water intake following central cholinergic stimulation have been incompletely characterized. OBJECTIVES: To examine whether drinking and brain Fos-immunoreactivity (ir) induced in rats by central administration of bethanecol is reversed by either the preferential M1 antagonist pirenzepine, the M3 antagonist 4-DAMP, or their combination. METHODS: Male Sprague-Dawley rats were surgically implanted with cerebroventricular cannulae. The muscarinic agonist, bethanecol was used as the dipsogenic agent. Either nonselective (atropine) or selective muscarinic receptor antagonists were injected together with bethanecol to determine blockade of drinking. In parallel studies, Fos-ir was assessed in discrete brain regions. RESULTS: Bethanecol-induced drinking was completely blocked by atropine or by a combination of pirenzepine and 4-DAMP; these latter antagonists alone produced sub-total inhibition of drinking. In contrast, water intake induced by angiotensin II was unaffected by combination of pirenzepine and 4-DAMP. Fos-ir was induced by bethanecol in many brain regions previously implicated in body fluid regulation, including subfornical organ and the magnocellular supraoptic and paraventricular hypothalamic nuclei. Induced Fos-ir was substantially but not completely prevented by co-injection of either pirenzepine or 4-DAMP, but their combination did not seem markedly more effective than either alone. CONCLUSIONS: Drinking induced by brain muscarinic receptor stimulation seems to proceed by a combination of M1 and M3 receptor subtypes. Drinking induced by angiotensin II occurs independently of this mechanism. Fos-ir induced in fluid-related brain regions by bethanecol either uses additional receptor type(s) or is less easily blocked than drinking behavior.

Animals↗

PubMed2002

Adaptation to destabilizing dynamics by means of muscle cocontraction.

Adaptive control of wrist mechanics was investigated by means of destabilizing dynamics created by a torque motor. Subjects performed a 20 degrees movement to a 3 degrees target under the constraint that no motion should occur outside of the target zone once 800 ms had elapsed from movement onset. This constraint served as the minimum acceptable level of postural stability. The ability of subjects to modify their muscle activation patterns in order to successfully achieve this stability was investigated by creating three types of destabilizing dynamics with markedly different features: negative stiffness, negative damping, and square-wave vibration. Subjects performed sets of trials with the first type of destabilizing dynamics and were then required to adapt to the second and third. The adaptive response was quantified in terms of the rms electromyographic (EMG) activity recorded during various phases of the task. Surface EMG activity was recorded from three muscles contributing to wrist flexion and three muscles contributing to wrist extension. With negative stiffness, a significant compensatory increase in cocontraction of wrist flexor and extensor muscles was observed for slow movements, but there was little change in the muscle activity for rapid movements. With negative damping, muscle cocontraction was elevated to stabilize rapid movements, declining only gradually after the target was reached. For slow movements, cocontraction occurred only when negative damping was high. The response to square-wave vibration (10 Hz, +/-0.5 Nm), beginning at movement onset, was similar to that of negative damping, in that it resulted in elevated cocontraction. However, because the vibration persisted after the target was reached, there was no subsequent decrease in muscle activity. When the frequency was reduced to 5.5 Hz, but with the same torque impulse, cocontraction increased. This is consistent with greater mechanical instability. In summary, agonist-antagonist cocontraction was adapted to the stability of the task. This generally resulted in less of a change in muscle activity during the movement phase, when the task was performed quickly compared with slowly. On the other hand, the change in muscle activity during stabilization depended more on the nature of the instability than the movement speed.

Adaptation, Physiological↗

PubMed2003

Elbow impedance during goal-directed movements.

The mechanical properties and reflex actions of muscles crossing the elbow joint were examined during a 60-deg voluntary elbow extension movement. Brief unexpected torque pulses of identical magnitude and time-course (20-Nm extension switching to 20-Nm flexion within 30 ms) were introduced at various points of a movement in randomly selected trials. Single pulses were injected in different trials, some before movement onset and some either during early, mid, late or ending stages of the movement. Changes in movement trajectory induced by a torque pulse were determined over the first 50 ms by a nearest-neighbor prediction algorithm, and then a modified K-B-I (stiffness-damping-inertia) model was fit to the responses. The stiffness and damping coefficients estimated during voluntary movements were compared to values recorded during trials in which subjects were instructed to strongly co-contract while maintaining a static posture. This latter protocol was designed to help determine the maximum impedance a subject could generate. We determined that co-contraction increased joint stiffness greatly, well beyond that recorded under control conditions. In contrast, the stiffness magnitudes were quite small during routine voluntary movements, or when the subjects relaxed their limb. Furthermore, the damping coefficients were always significant and increased measurably at the end of movement. Reflex activity, as measured by EMG responses in biceps and triceps brachii, showed highly variable responses at latencies of 160 ms or greater. These reflexes tended to activate both elbow flexors and extensors simultaneously. These findings suggest that very low intrinsic muscle stiffness values recorded during point-to-point motion render an equilibrium point or impedance control approach implausible as a means to regulate movement trajectories. In particular, muscle that is shortening against inertial loads seems to exhibit much smaller stiffness than similarly active isometric muscle, although some degree of damping is always present and does not simply co-vary with stiffness. Although the limb muscles can be co-contracted statically or during movement with an observable increase in stiffness and even task performance, this control strategy is rarely utilized, presumably due to the greater energetic cost.

Confidence Intervals↗

PubMed2002

Adaptation of reflexive feedback during arm posture to different environments.

In this study we have examined the ability of the central nervous system (CNS) to use spinal reflexes to minimize displacements during postural control while continuous force perturbations were applied at the hand. The subjects were instructed to minimize the displacements of the hand from a reference position that resulted from the force perturbations. The perturbations were imposed in one direction by means of a hydraulic manipulator of which the virtual mass and damping were varied. Resistance to the perturbations came from intrinsic and reflexive stiffness, and from the virtual environment. It is hypothesized that reflexive feedback during posture maintenance is optimally adjusted such that position deviations are minimal for a given virtual environment. Frequency response functions were estimated, capturing all mechanical properties of the arm at the end point (hand) level. Intrinsic and reflexive parameters were quantified by fitting a linear neuromuscular model to the frequency responses. The reflexive length feedback gain increased strongly with damping and little with the eigenfrequency of the total combined system (i.e. arm plus environment). The reflexive velocity feedback gain decreased slightly with relative damping at the largest eigenfrequency and more markedly at smaller eigenfrequencies. In the case of highest reflex gains, the total system remained stable and sufficiently damped while the responses of only the arm were severely underdamped and sometimes even unstable. To further analyse these results, a model optimization was performed. Intrinsic and reflexive parameters were optimized such that two criterion functions were minimized. The first concerns performance and penalized hand displacements from a reference point. The second one weights afferent control effort to avoid inefficient feedback. The simulations showed good similarities with the estimated values. Length feedback was adequately predicted by the model for all conditions. The predicted velocity feedback gains were larger in all cases, probably indicating a mutual gain limiting relation between length and velocity afferent signals. The results suggest that both reflex gains seem to be adjusted by the CNS, where in particular the length feedback gain was optimal so as to maximize performance at minimum control effort.

Adult↗

PubMed1994

Median and ulnar nerve conduction studies: normative data for young adults.

Temperature control and standardized technique, along with consideration of age, height, finger circumference, and instrumentation is imperative for appropriate interpretation of electrodiagnostic studies. Normative data must be based on these factors in adequate numbers of healthy subjects. This study provides comprehensive normative electrodiagnostic data for the median and ulnar nerves. Forty-four subjects participated in this study. The median motor studies showed a motor distal latency (DL) of 3.2 (0.4)msec, and distal amplitude (DAMP) of 12.1 (3.8)mV and sensory studies showed a DL of 2.5 (0.2)msec, and DAMP of 31.4 (8.7) microV for the men and 52.4 (14.3)microV for the women. The ulnar motor studies showed a motor DL of 2.6 (0.3)msec, and DAMP of 12.6 (2.3)mV and sensory studies showed a DL of 2.4 (0.2)msec, and DAMP of 27.0 (7.8)microV for the men and 52.9 (13.9)microV for the women. Sidedness and handedness did not affect the nerve conduction parameters of this study. Aging changes for these nerves were minimal but more apparent for the median nerve. The most noticeable change with aging was the decrease in amplitude of the sensory nerve action potential.

Action Potentials↗

PubMed1988

Receptor binding profiles of some selective muscarinic antagonists.

The binding of hexahydrosiladifenidol, procyclidine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine) and AF-DX 116 to muscarinic receptors in the heart, ileum, urinary bladder, parotid gland and cerebral cortex from guinea pig was studied in competition experiments with (-)-[3H]QNB. The affinity of AF-DX 116 was higher in the heart than in the cortex and it was extremely low in the parotid gland. The affinities of hexahydrosiladefinidol, procyclidine and 4-DAMP were higher in the cortex and parotid gland than in the heart, bladder and ileum. Hexahydrosiladifenidol and 4-DAMP recognized two classes of muscarinic binding sites in the cortex. However, in contrast to functional data, binding results showed that 4-DAMP hexahydrosiladifenidol and procyclidine did not distinguish between the sites in the smooth muscles and those in the heart. Nevertheless, the present data support the view that the putative M2-receptors are heterogeneous, since the four drugs examined were found to distinguish between the muscarinic binding sites in the parotid gland and those in smooth muscles and heart.

Animals↗

PubMed1991

Pre- and postjunctional muscarinic receptor subtypes in dog airways.

To examine muscarinic receptor subtypes involved in cholinergically mediated contractions of the airway, we studied the effects of the M1-selective antagonist, pirenzepine, the M2-selective antagonist, AF-DX 116, the M3-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP) methiodide, and the non-selective antagonist, atropine, on acetylcholine (ACh)- and electrically induced contractions in dog bronchi and bronchioles. The relative potencies of the antagonists based on IC50 values of each antagonist for contractions induced by the two concentrations of ACh that produced 50% of the maximum (ED50) and the maximum (EDmax) contractions and the pA2 values were atropine greater than or equal to 4-DAMP methiodide greater than pirenzepine = AF-DX 116 in both the bronchi and bronchioles. The IC50 and pA2 values of each antagonist did not differ significantly between the bronchi and bronchioles. 4-DAMP methiodide significantly inhibited the contractile response to electrical field stimulation (EFS) at 5 Hz at concentrations that did not alter the contractile responses to exogenous ACh in both the bronchi and bronchioles, whereas pirenzepine, AF-DX 116 and atropine inhibited the EFS-induced contraction only at the concentrations that reduced the contraction induced by exogenous ACh. The present results suggest that the cholinergic contraction is mediated via the postsynaptic receptor M3, based on functional potencies of muscarinic antagonists and presynaptic receptor auto-facilitatory M3, based on the suppression of the contractile response to EFS by 4-DAMP methiodide in central and peripheral airways.

Acetylcholine↗

PubMed1995

In vivo and in vitro effects of muscarinic receptor antagonists on contractions and release of [3H]acetylcholine in the rabbit urinary bladder.

The functional effects of muscarinic receptor antagonists were examined in vivo and in vitro on the rabbit urinary bladder. Inhibitory effects on carbachol-evoked contractions of detrusor strips were pronounced for 4-diphenylacetoxy-N-methylpiperidine (4-DAMP; -logIC50: 8.64), p-fluoro-hexahydro-sila-diphenidol (pFHHSiD; 7.84) and atropine (8.27), while they were less pronounced for pirenzepine (6.62) and methoctramine (5.36). 4-DAMP and methoctramine increased 3H overflow from [3H]choline-labelled strips in response to electrical stimulation, contrary to pirenzepine, which decreased the overflow. Concomitant contractions were markedly reduced by 4-DAMP and by pirenzepine, but not by methoctramine. The -logIC50 estimations for atropine-sensitive electrically evoked contractions revealed methoctramine (4.85) to be less potent on nerve-evoked contractions than on carbachol-evoked contractions, in contrast to pirenzepine (7.15) and 4-DAMP (9.15). The effects of the antagonists in anaesthetized rabbits resembled those in vitro. Thus, muscarinic receptors in the rabbit urinary bladder are heterogeneous; prejunctional facilitatory (M1) and inhibitory (M2) for acetylcholine release, and postjunctional muscarinic M3 receptors mediating contractile responses.

Acetylcholine↗

PubMed1988

Leishmania amazonensis: acidic organelles in amastigotes.

Leishmania amastigotes are intracellular protozoan parasites which exclusively invade cells of the macrophage series and multiply within phagolysosomes. Recent studies showed that intracellular and isolated amastigotes of L. amazonesis are killed by amino acid esters which appear to be trapped within as yet unidentified, possibly acidified, "lysosome-like" parasite compartments and cleaved by hydrolytic enzyme(s) (M. Rabinovitch, V. Zilberfarb, and C. Ramazeilles, 1986, Journal of Experimental Medicine 163, 520-535). In the present study, we have localized acidic compartments of Leishmania amastigotes using as a probe the weak base 3-(2,4 dinitroanilino)-3'-amino-N-methyldipropylamine (DAMP). This indicator, which can be detected within cells by light and electron microscopy using immunocytochemical immunocytochemical methods, mainly accumulates within megasomes and in dense inclusion vacuoles. With the help of quantitative assays to titrate cell-associated DAMP, it was found that (a) its uptake is temperature dependent and thus probably requires an energy supply, (b) the proton ionophore monensin partially inhibits the trapping of DAMP, and (c) monensin greatly increases its efflux from cells. These results, as well as those obtained by quantitative ultrastructural immunocytochemistry of cells incubated with DAMP in the absence or presence of monensin, show that megasomes and inclusion vacuoles have a low pH probably maintained by an active process. Furthermore, confirming the report of H. F. Hassan and G. H. Coombs (1987, Molecular and Biochemical Parasitology 23, 285-296) megasomes were found to display acid phosphatase activity at both light and electron microscope levels. This, together with the demonstration that megasomes are acidified, suggests that these organelles may be targets for amino acid derivatives.

Acid Phosphatase↗

PubMed1987

Identification of muscarinic M2 receptors on single muscle cells of the human and guinea pig intestine.

Muscle cells were isolated from the longitudinal muscle layer of guinea pig and human jejunum and used to identify the muscarinic receptor subtype (M1 or M2) that mediates contraction. Single muscle cells were anchored to the ceiling of a minichamber and their contraction was measured in response to acetylcholine, alone and in combination with three muscarinic antagonists: atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), and pirenzepine. Estimates of the inhibitory dissociation constants (Ki) were closely similar in human and guinea pig muscle cells (atropine 2.5-5 X 10(-11) M, 4-DAMP 1.9-2.9 X 10(10) M, and pirenzepine 8.2-9.5 X 10(-8) M). Thus, pirenzepine, a preferential M1 antagonist, was 1900-3280 times less potent than atropine and 279-500 times less potent than 4-DAMP. Comparative measurements on longitudinal muscle strips from guinea pig jejunum confirmed the greater potency of atropine and 4-DAMP relative to pirenzepine. Inactivation of muscarinic receptors on single muscle cells with dibenamine showed that only a small fraction of receptors was responsible for the response to acetylcholine. It was concluded that intestinal muscle cells contain a large reservoir of muscarinic M2 receptors that exhibit considerable spareness and heterogeneity.

Acetylcholine↗

PubMed1983

Rate theory models for ion transport through rigid pores. II. Time-dependent analysis of the single-file model with special reference to oscillatory behavior.

This article deals with the time-dependent evolution of the single-file movement of ions through channels of both biological and artificial membranes. The single-file transport process may exhibit not only the usual relaxation behaviour but also oscillatory behaviour as a steady state is approached after an initial perturbation. A necessary condition for the occurrence of oscillations is that the system acts sufficiently far from equilibrium. The occurrence of oscillations is due to the interactions within the transport system which are taken into account by the single-file model; these are the electrostatic repulsion between the ions being transported, and the competition of the ions for the free binding sites within the pore. Information about the strength of the interactions can be obtained by measuring the damping of the transport observables (e.g. the electric current): The stronger the inter-ionic repulsion, the more apparent the oscillatory behaviour will become. Furthermore, the damping is influenced by the microscopic structure of the transport system (i.e. the energy profile of the pores). With an increasing degree of microscopicity, i.e. with a decreasing number of binding sites and an increasingly irregular pore profile, the oscillations become more damped. However, a considerable oscillatory behaviour can only be predicted for pores with both a sufficiently regular structure and a sufficiently large number of binding sites. For this class of pores, however, the measurement of the damping represents an appropriate method of gaining information which could exceed that obtainable from the usual methods of measuring stationary quantities (e.g. stationary conductance). Moreover, our goal is to explain theoretically how the oscillatory behaviour can be interpreted in terms of the order inherent in the ionic movement, which is determined by both the external and internal forces and the microscopic properties of the system.

Binding Sites↗

PubMed1991

Determination of in vitro simulated blood cell velocity by laser-Doppler with state space methods.

In this paper a signal processing method based on an important tool of numerical analysis, the singular value decomposition (SVD), is used. This method is applied to the unprocessed output of a Laser-Doppler fluxmeter to obtain parameters that are more sensitive to blood velocity than to hematocrit. The SVD-based method utilizes the exponential shape of the frequency spectrum of the laser light scattered from the moving red blood cells and demonstrates an inverse relationship between the damping constant beta associated with the exponential shape and the blood velocity. This method was applied to samples of rat blood of several known hematocrit values that were rotated at different velocities on a turntable. The method extracted one dominant singular value from the spectra, indicating that the spectra can be modeled as a single exponential dominated by scatterings with a single moving red blood cell. A 68% change in inverse velocity resulted in a 50% change in the damping constant (hematocrit 29.5% vol). On the other hand, a 37% change in hematocrit resulted in a far smaller change in the damping constant beta of only 17%. Analysis of the extracted parameters shows that the damping constants are far more influenced by blood velocity than by blood hematocrit.

Animals↗

PubMed1993

Role of spinal and supraspinal muscarinic receptors in the expression of morphine withdrawal symptoms in the rat.

Previous studies in this laboratory have demonstrated that prior intracerebroventricular (i.c.v.) administration of the muscarinic antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) in morphine dependent rats significantly attenuates the development of cardiovascular and certain behavioral responses precipitated by the opiate antagonist, naloxone. The purpose of this study was to determine whether both supraspinal and spinal cholinergic neurons are involved in the expression of withdrawal symptoms. Employing localized (i.c.v. or intrathecal, i.t.) infusions of muscarinic antagonists, it was determined that a significant antiwithdrawal action could be produced through both an inhibition of supraspinal and spinal cholinergic neurons. Pharmacological difference emerged regarding the antiwithdrawal potential of 4-DAMP and the partially M1 selective antagonist, pirenzepine. While our previous studies had revealed that pirenzepine had essentially no antiwithdrawal activity when administered by the i.c.v. route, in the present study, pirenzepine evoked a marked antiwithdrawal action by the i.t. route, significantly inhibiting both cardiovascular and behavioral signs of withdrawal. In contrast, 4-DAMP which was effective by the i.c.v. route (especially for the cardiovascular symptoms), elicited no antiwithdrawal action by the i.t. route. As a muscarinic antagonist (ability to block the pressor response to central injection of carbachol) 4-DAMP was equally active by i.c.v. or i.t. injection. However, pirenzepine was clearly more effective in this regard by the i.t. route. These results are consistent with ability of muscarinic antagonists to offer significant anti-morphine withdrawal activity at both supraspinal and spinal locations. They also suggest that different muscarinic systems, possibly different receptor subtypes, mediate the expression of morphine withdrawal symptoms within the two regions of the CNS.

Animals↗

PubMed1985

Vesicles and cisternae in the trans Golgi apparatus of human fibroblasts are acidic compartments.

Recently we demonstrated that low-pH compartments can be visualized with the electron microscope using a basic congener of dinitrophenol, 3-(2,4-dinitroanilino)-3'-amino-N-methyldipropylamine (DAMP), which concentrates in acidic compartments and can be detected by immunocytochemistry with a monoclonal anti-dinitrophenol antibody. We now report that DAMP also accumulates in cisternae and vesicles associated with the trans face of the Golgi apparatus. DAMP rapidly leaves this compartment when cells are incubated with the ionophore monensin, which indicates that accumulation is due to the acidic pH in this compartment. Using indirect protein A-gold immunocytochemistry, we localized fibronectin, a major secretory protein in fibroblasts, to the trans Golgi vesicles that took up DAMP. Therefore, the trans cisternae of the Golgi apparatus and forming secretory vesicles have an acidic pH.

Animals↗