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Neural representations of temporally asymmetric stimuli in the auditory cortex of awake primates.

The representation of rapid acoustic transients by the auditory cortex is a fundamental issue that is still unresolved. Auditory cortical neurons have been shown to be limited in their stimulus-synchronized responses, yet the perceptual performances of humans and animals in discriminating temporal variations in complex sounds are better than what existing neurophysiological data would predict. This study investigated the neural representation of temporally asymmetric stimuli in the primary auditory cortex of awake marmoset monkeys. The stimuli, ramped and damped sinusoids, were systematically manipulated (by means of half-life of the exponential envelope) within a cortical neuron's presumed temporal integration window. The main findings of this study are as follows: 1) temporal asymmetry in ramped and damped sinusoids with a short period (25 ms) was clearly reflected by average discharge rate but not necessarily by temporal discharge patterns of auditory cortical neurons. There was considerable response specificity to these stimuli such that some neurons were strongly responsive to a ramped sinusoid but almost completely unresponsive to its damped counterpart or vice versa. Of 181 neurons studied, 140 (77%) showed significant response asymmetry in at least one of the tested half-life values of the exponential envelope. Forty-six neurons showed significant response asymmetry over all half-lives tested. Sustained firing, commonly observed under awake conditions, contributed to greater response asymmetry than that of onset responses in many neurons. 2) A greater proportion of the neurons (32/46) that exhibited significant overall response asymmetry showed stronger responses to the ramped sinusoids than to the damped sinusoids, possibly contributing to the difference in the perceived loudness between these two classes of sounds. 3) The asymmetry preference of a neuron to ramped or damped sinusoids did not appear to be correlated with its characteristic frequency or minimum response latency, suggesting that this is a general phenomenon that exists across populations of cortical neurons. Moreover, the intensity of the stimuli did not have significant effects on the measure of the asymmetry preference based on discharge rate. 4) A population measure of response preference, based on discharge rate, of cortical neurons to the temporally asymmetric stimuli was qualitatively similar to the performance of human listeners in discriminating ramped versus damped sinusoids at different half-life values. These findings suggest that rapid acoustic transients embedded in complex sounds can be represented by discharge rates of cortical neurons instead of or in the absence of stimulus-synchronized discharges.

Acoustic Stimulation↗

Characterization of muscarinic receptor subtypes on rat pancreatic acini: pharmacological identification by secretory responses and binding studies.

In order to identify subtypes of muscarinic receptor on the rat pancreas, the effects of new muscarinic receptor antagonists, [11-[[2-(diethylamino)-methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) and 4-diphenylacetoxy-N-methylpiperadine-methiodide (4-DAMP), on amylase secretion stimulated by carbachol and binding of [3H]quinuclidinyl benzilate (QNB) were evaluated using isolated rat pancreatic acini. Atropine, pirenzepine, AF-DX 116 and 4-DAMP inhibited carbachol-stimulated amylase release in a dose-dependent manner. All these antagonists caused a concentration-dependent rightward shift of the dose-response curve for carbachol-stimulated amylase release without altering the maximal response. Schild plots revealed that pA2 values for atropine, pirenzepine, AF-DX 116 and 4-DAMP were 9.15, 6.78, 6.09 and 8.79, respectively. Every slope of Schild plots was not different from unity, suggesting that these antagonists act as competitive inhibitors. These antagonists also inhibited the binding of [3H]QNB in a dose-dependent manner. The inhibition constants were 1.21 x 10(-9) M (atropine), 1.26 x 10(-7) M (pirenzepine), 0.57 x 10(-6) M (AF-DX 116) and 2.75 x 10(-9) M (4-DAMP). Thus, the order of inhibitory potencies was atropine > or = 4-DAMP > pirenzepine > AF-DX 116. These findings suggest that 4-DAMP-sensitive M3 receptor may play an important role in the pancreatic exocrine functions.

Amylases↗

Muscarinic receptor subtypes in human nasal mucosa: characterization, autoradiographic localization, and function in vitro.

Muscarinic receptors play important roles in the regulation of glandular secretion and vasomotor tone in human nasal mucosa. M1, M2, and M3 muscarinic receptor subtypes were pharmacologically characterized in human inferior turbinates by receptor-binding assays using [3H](-)quinuclidinyl benzilate (QNB, identifies total muscarinic receptors) and [3H]-pirenzepine (PZ). Receptors were localized by autoradiography, and their function examined in vitro by assaying mucus secretion from cultured nasal mucosal explants. In competition assays, PZ was employed as a selective muscarinic antagonist for M1 receptors, gallamine and AF-DX 116 for M2 receptors, and 4-DAMP for M3 receptors. These ligands are selective at low nanomolar concentrations, but can interact with other muscarinic receptors at higher concentrations. It is not known if they can interact with putative M4 and M5 muscarinic receptor subtypes. Using [3H](-)QNB, total muscarinic receptor binding was 688.4 +/- 49.6 fmol/mg protein (Bmax), with a Kd of 1.47 +/- 0.13 nM. [3H]-PZ bound to 45% of the total QNB binding sites. In competition experiments, 4-DAMP displaced [3H](-)QNB with the lowest IC50, followed by PZ and AF-DX 116. Autoradiograms demonstrated that [3H](-)QNB binding was completely displaced by 4-DAMP, partially displaced by PZ, but not displaced by gallamine or AF-DX 116, and suggested that M1 and M3 subtypes coexist in submucosal glands. The localization of M1 receptors on submucosal glands was confirmed by direct labeling with [3H]-PZ. [3H]-PZ also labeled vessels, but with a low silver grain density. Autoradiographic [3H]-QNB binding was displaced by 4-DAMP and atropine, but not by PZ, gallamine, or AF-DX 116. In studies of mucus secretion in vitro, 4-DAMP significantly inhibited methacholine-induced secretion. Although less effective, PZ also had significant inhibitory effects. Neither gallamine nor AF-DX 116 had any inhibitory effect. M1 receptors (PZ binding sites) may regulate glandular secretion while M3 receptors (4-DAMP binding sites) may regulate glandular secretion and vasomotor tone in human nasal mucosa.

Autoradiography↗

Indoor exposures and recurrent wheezing in infants: a study in the BAMSE cohort.

AIM: The aim of this study was to examine the relationship between indoor exposures and the home environment, and the development of recurrent wheezing during infancy. METHODS: A birth cohort, comprising 4089 children, was followed. Information on exposures was obtained shortly after birth, and episodes of wheezing were recorded when the infants were 1 and 2 y of age. In a nested case-control study, 181 infants were enrolled, who had three or more reported episodes of wheezing after 3 mo of age combined with either use of inhaled steroids or symptoms of bronchial hyper-reactivity, and 359 age-matched controls. Home inspections were performed during the winter following enrolment, and indoor conditions were measured. RESULTS: Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated. The OR for recurrent infant wheezing associated with signs of dampness reported prospectively by parents was 1.4 (0.9-2.2), and the OR for observed signs of dampness at home inspections was 1.6 (1.0-2.5). A trend was found in the risk of recurrent wheezing in relation to the number of indicators of dampness: OR 1.3 (0.8-2.2) for one sign of dampness and OR 2.7 (1.3-5.4) for three or more signs of dampness. Newly painted surfaces in the child's bedroom was associated with an increased OR for recurrent wheezing: 1.7 (1.3-2.6). CONCLUSION: Indicators of dampness, as well as recently repainted interior surfaces, appear to be associated with recurrent infant wheezing, with a strengthened effect of combined indoor exposures.

Air Pollution, Indoor↗

Gentamicin nucleotidyltransferase. Stereochemical inversion at phosphorus in enzymatic 2'-deoxyadenylyl transfer to tobramycin.

Gentamicin nucleotidyltransferase-catalyzed reaction of (Sp)-[alpha-17O]dATP with tobramycin produced 2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin. The configuration at phosphorus in this product was shown to be Rp by chemical degradation to chiral [17O, 18O]dAMP using a stereochemically defined procedure, and determination of the configuration at phosphorus in this product. Periodate-base treatment of 2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin followed by NaBH4 reduction produced (2-glyceryl)-[17O]dAMP, which upon snake venom phosphodiesterase-catalyzed hydrolysis in H(2)18O produced [17O,18O] dAMP. The configuration at phosphorus in this product was shown to be S by enzymatic phosphorylation to [17O,18O]dATP, adenylylcyclase (Bordetella pertussis)-catalyzed cyclization to 3',5'-cyclic [17O,18O]dAMP, and 31P NMR analysis of the ethyl esters. Since snake venom phosphodiesterase-catalyzed hydrolyses proceed with retention of configuration at phosphorus, (Sp)-[17O,18O]dAMP must have been produced from (Rp)-(2-glyceryl)-[17O]dAMP; and since the chemical degradation to the latter compound did not involve cleavage of any bonds to phosphorus, the initial enzymatic product must have been (Rp)-2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin. Therefore, nucleotidyl transfer catalyzed by gentamicin nucleotidyl-transferase proceeds with inversion of configuration at phosphorus, and the reaction mechanism involves an uneven number of phosphotransfer steps. Inasmuch as this is an uncomplicated two-substrate group transfer reaction, the mechanism probably involves direct nucleotidyl transfer from the nucleoside triphosphate to the aminoglycoside. The B. pertussis adenylylcyclase reaction was shown to proceed with inversion at phosphorus, as has been established for other adenylylcyclases.

Adenylyl Cyclases↗

Studies on the mechanism of DNA polymerase alpha. Nascent chain elongation, steady state kinetics, and the initiation phase of DNA synthesis.

A detailed study of the mechanism of nascent chain elongation and of steady state kinetics of purified mouse DNA polymerase alpha has been conducted. Polymerization was examined using a model replication system of poly(dT) as template, oligo(rA) as primer, and dATP as nucleotide substrate, and the probability of chain termination was determined by measurement of the precise chainlength of the products. Reactions were conducted under conditions where products were not utilized as primer. Product chainlength analysis indicated that alpha-polymerase acted in a processive fashion, elongating the primer by the stepwise addition of up to 20 dAMP residues before dissociating. The probability of termination after each dAMP addition depended upon the chainlength of the product and upon the presence of several agents; spermine, spermidine, putrescine, nalidixic acid, or PPi caused a marked increase in termination after the first dAMP addition, and conversely, mouse helix destabilizing protein-1 caused the enzyme to continue extending the same product chain until 18 to approximately 35 dAMP residues had been added. From these and other data, it is concluded that the kinetic mechanisms of termination after the first dAMP addition and after subsequent dAMP additions are different. With this information on how alpha-polymerase elongates a nascent primer(dA)n molecule, a kinetic model and appropriate steady state rate equations were obtained for analysis of substrate initial velocity data and termination probabilities. The substrate kinetic patterns and PPi product inhibition results were consistent with the ordered Ter Ter mechanism Bi Uni Uni Bi Ping Pong proposed in the model, and the model also permits a rational explanation for the differences in termination probability and for the fact that substrate initial velocity plots were linear even though multiple residues of dATP combined with the enzyme during each catalytic cycle. In addition, the results suggest that a rate-limiting step in the steady state occurs at the transition between initiation and elongation, and that higher levels of template.primer increase the rate of this step. This secondary effect of template.primer is discussed in relation to other polymer-forming enzymes, and various kinetic mechanisms which require the presence of two template.primer-binding sites, effector and catalytic, are discussed for their fit to the experimental data.

DNA Polymerase II↗

Contractile roles of the M2 and M3 muscarinic receptors in the guinea pig colon.

The contractile roles of the M2 and M3 muscarinic receptors were investigated in guinea pig longitudinal colonic smooth muscle. Prior treatment of the colon with N-(2-chloroethyl)-4-piperidinyl diphenylacetate (4-DAMP mustard) (40 nM) in combination with [[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one (AF-DX 116) (1.0 microM) caused a subsequent, irreversible inhibition of oxotremorine-M-induced contractions when measured after extensive washing. The estimate of the degree of receptor inactivation after 2 hr (97%) was not much greater than that measured after 1 hr (95%), which suggests that both 4-DAMP mustard-sensitive and -insensitive muscarinic subtypes contribute to the contractile response. Pertussis toxin treatment had no significant inhibitory effect on the control contractile response to oxotremorine-M, but caused an 8.8-fold increase in the EC50 value measured after a 2-hr treatment with 4-DAMP mustard. These results suggest that, after elimination of most of the M3 receptors with 4-DAMP mustard, the contractile response can be mediated by the pertussis toxin-sensitive M2 receptor. After pertussis toxin treatment, the kinetics of alkylation of muscarinic receptors in the colon were consistent with a single, 4-DAMP mustard-sensitive, M3 receptor subtype mediating the contractile response. When measured after a 2-hr treatment with 4-DAMP mustard and in the presence of histamine (0.30 microM) and either forskolin (10 microM) or isoproterenol (0.60 microM), the contractile responses to oxotremorine-M were pertussis toxin-sensitive and potently antagonized by the M2 selective antagonist, AF-DX 116. Collectively, our results indicate that the M2 receptor elicits contraction through two mechanisms, a direct contraction and an indirect contraction by preventing the relaxant effects of cAMP-generating agents.

Animals↗

Upstream stenosis. Its diagnosis by Doppler signals from the femoral artery.

Transcutaneous femoral artery Doppler signals were measured with a 10-MHz pencil probe in 263 lower limbs of 135 patients. The Doppler waveforms were compared with arteriograms in 125 limbs with lower-limb ischemia and in 138 controls in the detection of minor (< 50%) and major (> 50%) iliac-artery stenosis. Doppler maximum velocity-time waveforms were obtained using a maximum frequency follower, and the wave-form shape was analyzed using a Laplace transform (LT) to produce a coefficient, the LT damping. Pulsatility index (PI) was also calculated. In 62 limbs with minor artery disease, mean LT damping was significantly greater than normal (0.5 +/- 0.15 vs 0.33 +/- 0.06; P < .001). In 63 limbs with major iliac stenosis, mean LT damping was higher still (0.78 +/- 0.16; P < .02). The LT damping was not affected by increased distal impedance and there was a good correlation with iliac stenosis in 65 limbs with an occluded superficial femoral artery (r = -0.73). The results with PI were inferior at every grade of severity of iliac disease when assessed by receiver-operator characteristic curves. These results suggest that LT damping is a sensitive method of analyzing femoral Doppler signals in the noninvasive detection of iliac artery stenosis.

Arterial Occlusive Diseases↗

Longitudinal models for analysis of respiratory function.

We compare the results of fitting three longitudinal models, two autoregressive models (the serial correlation model and a damped autoregressive model) and a compound symmetry model, to data on a cohort of 1154 adult men in Boston. The serial correlation model assumes that the error terms are autocorrelated with correlation of the form lambda t for visits t years apart while the damped autoregressive assumes that the correlation between error terms of observations t years apart is of the form lambda t theta. The compound symmetry model assumes that the errors are correlated, with the same correlation regardless of how far apart observations are in time. These three models are all related in that the serial correlation and compound symmetry models are particular cases of the damped autoregressive models (that is, theta = 1 corresponds to the serial correlation model and theta = 0 corresponds to the compound symmetry model). For current smokers, the damped autoregressive model provided a significantly better fit than either of the other two models (p < 0.001); for never smokers the damped autoregressive and compound symmetry models were almost identical with both providing a significantly better fit than the serial correlation model (p < 0.001).

Adult↗

Spectral fitting of NMR spectra using an alternating optimization method with a priori knowledge.

As alternatives to the fast Fourier transform, advanced parametric methods based on the damped sinusoidal data model have been devised to better quantify the nuclear magnetic resonance (NMR) spectroscopy time-domain data. Previously, linear prediction (LP) fitting methods using Householder triangularization and singular value decomposition (SVD) techniques have been applied to the NMR spectroscopy data analysis. In this paper, we propose an alternating optimization method to quantify the time-domain NMR spectroscopy data. The proposed algorithm uses the a priori knowledge of the possible frequency intervals of the damped sinusoids to obtain more accurate parameter estimates when the NMR spectroscopy data are obtained under low signal-to-noise ratio conditions and the peaks are close together. None of the LP and SVD type of methods can use such approximate a priori knowledge. We have shown with measured NMR spectroscopy data that the proposed algorithm can be used to obtain accurate parameter estimates of frequencies, amplitudes, and damping ratios of the damped sinusoids and therefore the ultimate fit of the spectrum by using the a priori knowledge about the possible frequency intervals of the damped sinusoids.

Algorithms↗

The Impact of Environmental Variation on Demographic Convergence of Leslie Matrix Population Models: An Assessment Using Lyapunov Characteristic Exponents

In a constant environment, the rate of convergence of a density-independent Leslie matrix model to stable age distribution is determined by the damping ratio (the ratio of the absolute magnitudes of the first and second eigenvalues of the projection matrix). In a stochastic environment, the difference between the first two Lyapunov exponents is known to be analogous to the logarithm of the damping ratio, but there has been no systematic investigation of the consequences of enviromnental variation on convergence rates. In this study, the Lyapunov spectrum has been calculated for a wide variety of density-independent projection matrices subject to random variations in vital rates. This allows the impact of these random variations on convergence rates to be assessed. For rapidly convergent life histories, stochastic variation leads to a decrease in convergence rate. For life histories which are slow to converge, stochastic variation speeds up convergence. These effects are, however, relatively minor, and the value of the damping ratio for the mean matrix is a good predictor of the damping ratio in a stochastic environment. Consequently, when only an approximate indication of convergence rates is needed, the damping ratio for the mean projection matrix gives a very good guide. Detailed calculations of the Lyapunov spectrum would only be necessary to make comparisons between similar life histories or if very precise information on convergence rates were needed.

Journal Article↗

Compensation for mechanically unstable loading in voluntary wrist movement.

In order to study the roles of muscle mechanics and reflex feedback in stabilizing movement, experiments were conducted in which healthy human subjects performed targeted wrist movements under conditions where the damping of the wrist was reduced with a load having the property of negative viscosity. If the movement speed and negative viscosity. If the movement speed and negative viscosity were sufficiently high, the wrist oscillated for several hundred milliseconds about the final target position. Subjects increased the activation of both wrist flexor and extensor muscles to increase joint stiffness to damp the oscillations. With practice, both the tendency to oscillate and the level of muscle activation were reduced. A small bias torque in either direction, added to the negative viscosity, enhanced the oscillations as well as the amount of flexor and extensor muscle activation during the stabilization phase of fast movements. The tendency for the wrist to oscillate was also seen during slow movements where the oscillations were superimposed upon the voluntary movement. We suggest that this reduction in mechanical stability is primarily of reflex origin. As wrist stiffness increases, the natural frequency of the wrist also increases, which in turn produces an increase in the phase lag of the torque generated by the myotatic reflex with respect to wrist angular velocity, effectively reducing damping. The oscillation frequency was often close to a critical frequency for stability at which torque, due to the myotatic reflex, lagged angular velocity by 180 degrees (6-7.5 Hz). Nevertheless, subjects were able to damp these oscillations, probably because the torque due to intrinsic muscle stiffness (in phase with position and hence lagging velocity by only 90 degrees) dominated the torque contribution of the myotatic reflex. Increasing stiffness with declining oscillation amplitude may also have contributed significantly to damping.

Adult↗

The force-velocity curve in passive whole muscle is asymmetric about zero velocity.

The force-velocity property of passive muscle was investigated to determine if a discontinuity of slope occurred at zero velocity. Isolated, unstimulated whole frog sartorius muscles were subjected to constant-velocity stretches and releases using a servo-controlled lever. The force due to damping (delta T) was calculated by subtracting the tension measured at a very low speed (1.0 mm s-1) from the tension measured at the same length while the muscle was shortening or lengthening at a particular test speed. The experiments were performed over a range of speeds at each of several lengths and at two temperatures. For comparison, the same experiments were performed using a strip of pure latex rubber and a steel spring. Curves showing the magnitude of delta T vs velocity were nearly symmetric about the zero-velocity axis for the steel spring and the rubber strip, but were markedly asymmetric for passive muscle, showing a positive delta T for lengthening at all speeds that was between four and 11 times the negative delta T for shortening at the same speed, depending on the temperature and initial stretch length. The force due to damping at a given speed increased with extension above the rest length in passive muscle but decreased with increasing length in experiments using the latex strip. Predictions obtained from a mathematical model based on a damping element in series with a lightly damped spring were fitted to the experimental measurements of delta T vs velocity. The damping parameter provisionally representing interfilamentary sliding was between six and 12 times larger for lengthening than for shortening.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Dexfenfluramine lacks amphetamine-like abuse potential.

1. The amphetamine-like abuse potential of dexfenfluramine (dFEN) was evaluated using drug discrimination and self-administration procedures. 2. Male Fischer rats were trained to discriminate either dFEN (1.0 mg/kg) or d-amphetamine (dAMP; 1.0 mg/kg) from saline in a two-choice discrete-trial avoidance paradigm. 3. In dAMP-trained rats, dFEN (0.5-4.0 mg/kg) engendered almost exclusively saline-appropriate responding. In dFEN-trained rats, dAMP (1.0-4.0 mg/kg) engendered entirely saline-appropriate responding in 3 of 6 rats and intermediate levels of dFEN-appropriate responding in the remaining animals. 4. Potential reinforcing effects of dFEN were also evaluated in 3 male rhesus monkeys trained to self-administer cocaine (i.v.) during daily 60 min sessions under a fixed-ratio (FR)-10 schedule. 5. Various doses of dFEN (30-1000 micrograms/kg/infusion) and dAMP (10 micrograms/kg/infusion) were substituted for cocaine in 4 consecutive daily sessions. In all subjects, dFEN maintained rates of self-administration within the range of rates maintained by saline and considerably below those maintained by cocaine and dAMP. Furthermore, the within-session distribution of responding with dFEN resembled that produced by saline. 6. Taken together, these results strongly suggest that dFEN will not have amphetamine-like abuse potential in humans.

Amphetamine↗

Quantitative multichannel EEG measure predicting the optimal weaning from ventilator in ICU patients with acute respiratory failure.

OBJECTIVE: The objective of this study was to develop a novel quantitative multichannel EEG (qEEG) based analysis method, called Global Field Damping Time (GFDT), in order to detect potential EEG changes of patients admitted to the ICU with acute respiratory failure, and correlate them to the patients' recovery outcome predicting the optimal time-point to disconnect the patient from mechanical ventilation. METHODS: Twenty-nine adult patients with acute respiratory failure out of 98 admitted to the Intensive Care Unit of Saint Paul General Hospital were enrolled, and among them only 15 completed the study. The patients were classified in 3 groups according to their outcome after 3 months follow-up. The patients were intubated with fraction of inspired oxygen (FiO2) of 100%. Neurological Deficit Scores (NDS) were measured 24 h after intubation to assess patients' neurological condition. Twenty-four hours after patient's intubation, FiO2 was decreased to 40% (weaning session), followed by a 5 min early recovery session, a 5 min recovery 1 session and a 5 min recovery 2 session. EEG recordings were performed during this experimental procedure. Multichannel EEG segments were processed and fitted into a multivariate autoregressive (mAR) model, and single channel EEG segments into a scalar autoregressive (sAR) model. The mAR and the sAR models of arbitrary order p were decomposed into mp and p oscillators and relaxators, respectively. Damping time of each oscillator and each relaxator, and the Global Field Damping Time (GFDT) as a weighted damping time were estimated for both mAR and sAR models. RESULTS: A statistically significant increase of mAR model's GFDT during the weaning session was observed in the subjects of all groups. Comparing the 3 patients' groups, statistically significant differences for mAR model's GFDT were observed for the weaning and early recovery session. Linear regression analysis between NDS and mean mAR model's GFDT showed statistical significance during weaning session, early recovery session, and recovery 1 session. There was no statistical significance for SaO2 in the regression analysis with NDS. The sAR model's GFDT presented worst results in comparison with the mAR modelling GFDT in the identification of hypoxic conditions during weaning session and in the discrimination of patients with acute respiratory failure according to their neurological outcome. CONCLUSIONS: Global Field Damping Time as correlated to the patients' neurological outcome appears to be a simple, compact, and substantial novel indicator of cerebral hypoxia and a potential predictor of the optimal time-point to disconnect the patient from the ventilator. SIGNIFICANCE: Quantitative EEG seems to be an important tool for ICU clinicians assisting them to decide for the patients' optimal time-point to disconnect the patient from the ventilator.

Acute Disease↗

Functional characterization of peripheral muscarinic subtypes in anesthetized cats.

This investigation was undertaken to characterize the muscarinic receptor subtypes involved in methacholine-induced vasodilation, vagal bradycardia, neurally-evoked sudomotor responses and sympathetic muscarinic ganglionic transmission in anesthetized cats. Dose-response curves were constructed using the putatively selective antagonists pirenzepine (M1), gallamine (M2) and 4-DAMP (M3: 4-diphenyl-acetoxy-N-methylpiperidine) and compared with the non-selective blocker, atropine. Methacholine hypotension and evoked sudomotor responses exhibited an M3 muscarinic receptor profile with the following potency relationships: atropine > or = 4-DAMP > pirenzepine >> gallamine. Vagal bradycardia (M2) was antagonized by gallamine and exhibited a lower relative sensitivity to 4-DAMP when corrected for atropine effect. Pirenzepine was inactive in inhibition of bradycardia but was highly potent against transmission in the sympathetic ganglion (M1) with the following potency relationships: atropine > or = pirenzepine > 4-DAMP >> gallamine. In comparison with atropine, 4-DAMP exhibited a significantly lower potency for M1 and M2 muscarinic receptors as compared to its effect on the M3 muscarinic receptor subtypes.

Animals↗

Characterization of muscarinic receptors mediating the contraction of the urinary detrusor muscle in cynomolgus monkeys and guinea pigs.

We have characterized in vitro the muscarinic receptors mediating the contraction of the detrusor muscle in Cynomolgus monkeys and guinea pigs using carbachol as the agonist and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M3-selective), methoctramine (M2-selective) and pirenzepine (M1-selective) as the antagonists. Carbachol induced a concentration-dependent contraction of the detrusor muscle of monkey and guinea pig yielding similar pD2 values of 6.67+/-0.03 (n=50) and 6.77+/-0.06 (n=36), respectively. In the detrusor muscle of Cynomolgus monkey, all antagonists produced a concentration-dependent inhibition of carbachol-induced contractions, without decreasing the maximal response. Schild plot analysis yielded slopes not different from unity for all antagonists. The order of antagonist potency was: 4-DAMP (pA2=8.96)>pirenzepine (pA2=6.66)>methoctramine (pA2=6.03), suggesting that M3 receptors have a dominant role in mediating detrusor contraction. In the detrusor muscle of the guinea pig, 4-DAMP and pirenzepine, but not methoctramine, produced a concentration-dependent inhibition of the carbachol-induced contractions, without decreasing the maximal response. Schild plot analysis yielded a slope not different from unity for 4-DAMP and pirenzepine. 4-DAMP (pA2=9.07) had a higher potency than pirenzepine (pA2=6.66), a finding consistent with previously published data. The present study shows that in Cynomolgus monkey stimulation of the M3 subtype is dominant in mediating detrusor contraction upon carbachol stimulation.

Animals↗

Biphasic transthoracic defibrillation causes fewer ECG ST-segment changes after shock.

STUDY OBJECTIVE: Electrocardiographic abnormalities are common after transthoracic defibrillation. ECG ST-segment changes are especially problematic after defibrillation and may indicate ischemic or shock-induced cardiac dysfunction after resuscitation. Biphasic defibrillation waveforms, compared with monophasic waveforms, diminish shock-induced cardiac dysfunction in laboratory preparations. This effect has not been validated in human subjects. We therefore evaluated in a prospective, blinded fashion the effect of biphasic and monophasic transthoracic defibrillation on the ECG ST segment in 30 consecutive patients during surgery for the implantation of a cardioverter-defibrillator. METHODS: In each patient two low-energy truncated biphasic transthoracic defibrillation shocks (115 and 130 J) were compared with a standard clinical 200 J monophasic damped-sine wave shock. The biphasic shocks and the damped-sine wave shock have been demonstrated to have equal defibrillation efficacy of 97%. Fifteen-second ECG signals recorded across transthoracic defibrillation electrodes were digitized before ventricular fibrillation induction and immediately after each defibrillation attempt. The ST segments 80 msec after the J point were analyzed in a blinded fashion by two reviewers. The ST-segment deflection, QRS-interval duration, QT interval, and heart rate after each therapy were compared with baseline values. RESULTS: ECG ST-segment elevation was significantly greater with the 200-J damped-sine waveform than with either biphasic waveform. The ECG ST-segment levels were -.55 +/- .36 at baseline, -.76 +/- .36 mm after internal shock, -.02-.36 mm after 115-J biphasic shock, .21 +/- .38 mm after 130-J biphasic shock, and 2.09 +/- .37 mm after 200-J damped-sine wave shock (P<.0001). QRS-interval duration, QT interval, and heart rate did not change significantly with any waveform. CONCLUSION: Transthoracic defibrillation with biphasic waveforms results in less postshock ECG evidence of myocardial dysfunction (injury or ischemia) than standard monophasic damped sine waveforms without compromise of defibrillation efficacy.

Adult↗