Biomedical subjects

F Dexter

Publications and source records attributed to F Dexter.

At least 127 records · Page 7Linked to original sources

PubMed1995

Dose-dependent effects of acute in vivo ethanol exposure on extracellular glutamate concentration in the cerebral cortex of the near-term fetal sheep.

The cerebral cortex is a target site of ethanol teratogenesis. L-Glutamate is a major excitatory neurotransmitter that plays an important neurotrophic role in brain development. It has been proposed that optimal function of the glutamate neuronal system is required for normal brain development; overactivation could lead to excitotoxic-induced neuronal injury, whereas underactivation could delay/restrict brain development. The objective of this study was to test the hypothesis that acute in vivo ethanol exposure alters basal glutamate release in the fetal cerebral cortex. The experimental approach involved measuring fetal cortical extracellular glutamate concentration using the technique of in vivo microdialysis. Near-term fetal sheep were chronically instrumented with a microdialysis probe placed in the parasagittal cortex. At 124 +/- 3 days of gestation, the effects of maternal intravenous infusion of 2 g or 4 g ethanol/kg maternal body weight or an equivalent volume of saline, given as four equally divided doses over 5 hr, on fetal cerebral cortical extracellular glutamate concentration were determined. None of the three treatment regimens produced fetal or maternal demise during the time course of the study. There was an ethanol dose-dependent increase, p = 0.005, in extracellular glutamate concentration in the fetal cerebral cortex. This increase was paroxysmal in nature and was not directly related to the fetal blood ethanol concentration. In view of the proposed role for glutamate in neuronal development, this apparent ethanol-induced increase in glutamate release may be important in the pathogenesis of ethanol teratogenesis involving the cerebral cortex.

Alcohol Drinking↗

PubMed1995

Temporal thresholds for hyperglycemia-augmented ischemic brain damage in rats.

BACKGROUND AND PURPOSE: Although acute hyperglycemia is known to increase global ischemic brain damage, the duration of ischemia necessary to elicit such an effect is unknown. Accordingly, an experiment was performed to determine the duration of forebrain ischemia at which hyperglycemia becomes a factor in histological and behavioral outcome in rats. METHODS: Fasted rats were anesthetized and prepared for forebrain ischemia. Before ischemia, rats received either intravenous saline (plasma glucose, 112 +/- 18 mg/dL) or glucose (plasma glucose, 343 +/- 50 mg/dL). After 4, 8, 12, or 15 minutes of ischemia (n = 12), recovery was allowed. Rats surviving 7 days underwent evaluation of motor function and then histological analysis of damage in the caudate putamen, hippocampal CA1, and substantia nigra pars reticulata. RESULTS: After 4 minutes of ischemia, damage was present in all structures. Only in the caudate putamen was hyperglycemia associated with worsened damage, but this did not result in seizures or death. After 8 minutes of ischemia, seizures occurred in 33% of hyperglycemic rats, and a hyperglycemic effect on damage in the CA1 and substantia nigra pars reticulata was observed. No seizures or mortality occurred in normoglycemic rats regardless of duration of ischemia. Longer durations of ischemia resulted in an increased incidence of seizures and mortality in hyperglycemic rats only. Among surviving rats, motor function was worsened in hyperglycemic rats after 12 minutes of ischemia. CONCLUSIONS: Hyperglycemia-augmented brain damage is evident after global ischemic insults as brief as 4 minutes and becomes critical to survival after 8 minutes of ischemia.

Animals↗

PubMed1994

Theoretical analysis predicts that respiratory sinus arrhythmia does not accurately measure efferent vagal activity during anesthesia.

The respiratory sinus arrhythmia (RSA) is an oscillation of cardiac cycle length (CCL) at the frequency of breathing. RSA is a non-invasive measure of efferent vagal activity, during controlled experimental conditions. Our goal is to assess whether existing theory predicts that RSA amplitude reliably measures efferent vagal activity during and after anesthesia. To do so we combine several existing mathematical models to predict the respiratory sinus arrhythmia. Computer simulation shows that for positive-pressure ventilation without spontaneous breathing efforts, increasing mean arterial pressure causes increase in efferent vagal activity, but not RSA amplitude. Therefore, for positive-pressure ventilation, RSA amplitude does not predict efferent vagal effects on CCL. In contrast, for spontaneous breathing, increasing mean arterial pressure causes increase in both efferent vagal activity and RSA amplitude. Therefore, during spontaneous breathing, RSA amplitude does predict efferent vagal activity. Nevertheless, RSA amplitude also depends on factors that have little effect on efferent vagal activity. For example, RSA amplitude is decreased by increasing respiratory rate or administering acetylcholinesterase and muscarinic antagonists. We conclude that current theory provides little or no justification for using RSA amplitude as a surrogate for efferent vagal activity during anesthesia.

Anesthesia, General↗

PubMed1994

Computer simulation of brain cooling during cardiopulmonary bypass.

A mathematical model of heat transport was used to analyze the effects of convection, metabolism, and conduction on the rate of brain cooling and the final brain temperature during cardiopulmonary bypass. Convection, a function of cerebral blood flow and arterial blood temperature, is by far the most important process to determine the rate of brain cooling. Arterial blood temperature almost entirely determines the final brain temperature. Although conduction (head surface cooling) has little effect on the rate of brain cooling or final brain temperature in adults, it may have moderate effects in infants. Brain metabolic heat production has insignificant direct effects on the rate of brain cooling and final brain temperature in both adults or infants. Computer simulation of convective cooling of the adult brain to 27 degrees C shows that, with routine perfusion techniques, brain temperature equilibration is rapid (16 minutes) and small brain-blood temperature gradients are achieved. Simulation of infant brain cooling to 17 degrees C shows that, to avoid excessive brain-blood temperature gradients, 22 to 26 minutes may be required to achieve brain temperature equilibration.

Adult↗

PubMed1994

Analysis of statistical tests to compare doses of analgesics among groups.

BACKGROUND: A common type of anesthesiologic study determines the effect of an intervention on the doses of analgesics given to groups of patients. The goal of this study was to evaluate the effectiveness of several appropriate statistical tests to examine the results of such studies. METHODS: Total doses of morphine received in a postanesthesia care unit were recorded for patients undergoing vitrectomy (244), laparoscopic cholecystectomy (104), or abdominal hysterectomy (143). Multiple simulated samples were then drawn from these data. These simulated samples were used in computer simulations of clinical trials comparing doses among groups. Assessments were made of the relative performance of the t test; analysis of variance; randomization; and the Mann-Whitney, Kruskal-Wallis, and chi-square tests for comparing doses of analgesics given to two or three groups of patients. RESULTS: The distributions were not normal. No statistical test incorrectly suggested that a difference existed among groups when there was no difference. A randomization test to compare two groups' means overestimated actual P values. A chi-square test, which compared fractions of patients in each group who received no morphine, had approximately the same power as the t or analysis of variance tests to detect differences among groups. Mann-Whitney or Kruskal-Wallis tests, for differences between two or more than two groups' medians, respectively, had the greatest power to detect difference(s) among groups. CONCLUSIONS: Mann-Whitney and Kruskal-Wallis are the best tests to find differences among doses of analgesics given to groups of patients.

Analgesics↗

PubMed1994

Minimum alveolar concentration for halothane in the rat is resistant to effects of forebrain ischemia and reperfusion.

BACKGROUND: Because glutamate antagonists can substantially alter the minimum alveolar concentration (MAC) of volatile anesthetics, glutamate has been implicated as an important neurotransmitter in processes contributing to the anesthetic state. Cerebral ischemia profoundly alters glutamatergic neurotransmission and thus may also alter halothane MAC. METHODS: Fasted rats were surgically prepared for forebrain ischemia. One half of the animals served as operative shams (n = 24). Remaining rats underwent 10 min of bilateral carotid occlusion combined with systemic hypotension (n = 24). In animals in both groups brain circulation was restored for 1 h, 24 h, or 7 days (n = 8). At each of these intervals, MAC for halothane was determined by the tail-clamp method. Histologic damage in the hippocampus, cortex, caudoputamen, and thalamus was measured in animals allowed to survive 7 days. RESULTS: Blood pressure, arterial blood gas tensions and pH, pericranial temperature, and plasma glucose values measured immediately before ischemia were similar among groups. Neither ischemia nor duration of reperfusion significantly altered halothane MAC as compared with operative shams (sham 1 h = 0.9 +/- 0.1 vol%, 24 h = 1.0 +/- 0.1 vol%, 7 days = 1.0 +/- 0.2 vol%; ischemia 1 h = 0.9 +/- 0.1 vol%, 24 h = 0.9 +/- 0.1 vol%, 7 days = 1.0 +/- 0.2 vol%). Histologic damage in the hippocampus and caudoputamen was severe in the ischemic group of animals. Mild injury was observed in the motor and cingulate cortex as well as the thalamus. There was no evidence of histologic injury in sham-operated animals. CONCLUSIONS: The absence of effect of ischemic forebrain injury on halothane MAC is consistent with findings made in other models of supratentorial cerebral injury. These results support the contention that anatomic foci for motor responses elicited during MAC determination are localized at levels caudal to the forebrain.

Animals↗

PubMed1994

Mathematical model of acetylcholine kinetics in neuroeffector junctions.

Acetylcholine (ACh) kinetics in neuroeffector junctions (NEJ) of the sinus node plays a key role in vagal control of heart rate. Prior studies have shown that the concentration of ACh ([ACh]) in NEJ appears to follow first-order linear kinetics. To find out the reason why, we examine mathematically diffusion, degradation, and receptor binding of ACh in NEJ. We identify seven conditions that potentially influence ACh kinetics. Because these conditions are satisfied for NEJ in the sinus node, 1) the nonlinearity of ACh binding to muscarinic receptors has little effect on [ACh]; 2) [ACh] does not depend on the distribution of acetylcholinesterase between the interstitial space and the pacemaker cells; 3) the interval from trough to subsequent peak [ACh] at the pacemaker cells is negligible; 4) the mean [ACh] at the pacemaker cells is proportional to the frequency of vagal activity multiplied by the amount of ACh released per vagal stimulus and divided by the rate coefficient of ACh degradation; and 5) [ACh] at pacemaker cells nearly follows first-order linear kinetics but does not at other sites in the NEJ. We conclude that earlier studies showed that [ACh] follows first-order linear kinetics, because they predicted [ACh] only at pacemaker cells. ACh kinetics at other sites in the NEJ, such as at nerve endings, is different.

Acetylcholine↗

PubMed1994

Blood warms as it flows retrograde from a femoral cannulation site to the carotid artery during cardiopulmonary bypass.

Hypothermia protects the brain from injury during cardiopulmonary bypass and hypothermic circulatory arrest. However, when the arterial cannula is at sites other than the ascending aorta, brain cooling before circulatory arrest may be incomplete, contributing to poor neurological outcome. The authors performed an experiment using a rabbit model of cardiopulmonary bypass with femoral arterial perfusion. Arterial perfusate and carotid artery temperatures were simultaneously measured in six rabbits undergoing cardiopulmonary bypass, three with femoral artery cannulation, and three with subclavian artery cannulation. The subclavian artery site was chosen as a surrogate for ascending aortic cannulation. Carotid blood temperature was 3.7 degrees C to 0.3 degree C warmer than arterial perfusate temperature during femoral arterial perfusion. The temperature difference decreased over time (p = 0.0007). The temperature gradient was significantly less (p = 0.002) when subclavian arterial perfusion was used. Carotid blood temperature was 1.1 degrees C to 0.0 degree C warmer than arterial perfusate temperature during subclavian cannulation. The authors conclude that when femoral perfusion cooling is used, blood is warmed as it flows in a retrograde direction in the descending aorta to the carotid artery.

Animals↗

PubMed1994

Glutamatergic antagonism: effects on lidocaine-induced seizures in the rat.

We tested the hypothesis that glutamate receptor antagonists increase the dose of lidocaine required to induce seizure activity. Sprague-Dawley rats were anesthetized with halothane in 40% O2/balance N2 and mechanically ventilated. After surgical preparation, halothane was discontinued. Normocapnia, normoxia, and normothermia were maintained. The electroencephalogram (EEG) and arterial blood pressure were monitored continuously. Rats were then randomized to one of six groups (control, one of three intravenous [i.v.] bolus doses of the competitive glutamate N-methyl-D-aspartate [NMDA] receptor antagonist CGS 19755, or one of two i.v. bolus and continuous infusion regimens of the competitive glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxalline [NBQX]). Thirty minutes after onset of CGS 19755 or NBQX administration (end-tidal halothane < 0.2%), rats received a continuous i.v. infusion of 1.5% lidocaine until EEG seizures occurred. The duration of the infusion (min) and total lidocaine dose (mg/kg) administered were recorded. CGS 19755 increased the lidocaine seizure threshold in a log-linear dose-dependent fashion (P < 10(-6)). The largest dose of CGS 19755 (112.5 mg/kg) increased the time to initial EEG seizure activity more than twofold (e.g., control = 12.6 +/- 2.6 min; CGS 19755 = 28.6 +/- 6.9 min). The effect of AMPA receptor antagonism was less obvious because treatment resulted in an EEG morphology dissimilar to that observed in the CGS 19755 or control groups. Our findings indicate that competitive NMDA receptor antagonists (e.g., CGS 19755) increase the dose of lidocaine required for seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Pulsatile versus nonpulsatile cardiopulmonary bypass. No difference in brain blood flow or metabolism at 27 degrees C.

BACKGROUND: It is unclear whether nonpulsatile perfusion adversely affects the brain. This study compared cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) betwen pulsatile and nonpulsatile cardiopulmonary bypass (CPB) in rabbits at 27 degrees C. METHODS: In experiment A, 24 anesthetized New Zealand white rabbits underwent pulsatile CPB at 27 degrees C, using alpha-stat acid-base management. Animals were randomized to three groups based upon the duration of the period of systolic ejection (100, 120, 140 ms) and were perfused for 20 min at each of three pulse rates (150, 200, 250 pulse/min), generating nine arterial pressure waveforms. Arterial pressure waveform, arterial and cerebral venous oxygen content, CBF (radiolabeled microspheres), and CMRO2 (Fick) were measured at the end of each 20-min period. In experiment B, 16 anesthetized rabbits were randomized to pulsatile (120-ms ejection period, 250 pulse/min) or nonpulsatile CPB at 27 degrees C. AFter 1 h, arterial pressure waveform, arterial and cerebral venous oxygen content, CBF and CMRO2 were measured. RESULTS: In experiment A, CBF and CMRO2 were independent of ejection period and pulse rate. Thus, all nine waveforms were physiologically equivalent. In experiment B, CBF did not differ between pulsatile and nonpulsatile bypass, 30 +/- 4 versus 32 +/- 5 ml.100 g-1.min-1, respectively. CMRO2 did not differ between pulsatile and nonpulsatile bypass, 1.7 +/- 0.2 versus 1.6 +/- 0.2 ml.100 g-1.min-1, respectively. CONCLUSIONS: During CPB in rabbits at 27 degrees C, neither CBF nor CMRO2 is affected by flow character.

Animals↗

PubMed1993

Hypothermic acid-base management does not affect cerebral metabolic rate for oxygen at 27 degrees C. A study during cardiopulmonary bypass in rabbits.

BACKGROUND: It has been contended that, during cardiopulmonary bypass at 27 degrees C, pH-stat management decreases cerebral metabolic rate for oxygen (CMRO2) more than alpha-stat management. In contrast, other studies have not found CMRO2 to differ between techniques. Using each animal as its own control, the authors assessed the effect of alpha-stat versus pH-stat management of CMRO2, cerebral blood flow (CBF), and brain oxygen extraction during cardiopulmonary bypass at 27 degrees C. METHODS: Fourteen New Zealand White rabbits, anesthetized with fentanyl and diazepam, underwent cardiopulmonary bypass at 27 degrees C (membrane oxygenator, centrifugal pump, and bifemoral arterial perfusion). Group 1 animals (n = 7) had alpha-stat management for the initial 65-70 min of bypass, and were then changed to pH-stat management for the remaining 30 min of bypass. Group 2 animals (n = 7) had pH-stat management for the initial 65-70 min of bypass, and were then changed to alpha-stat management for the remaining 30 min. Measurement of CBF (radiolabeled microspheres), CMRO2 (CBF x brain arterial-venous oxygen content difference), brain temperature, systemic hemodynamics, and arterial blood gases were made in each animal under both alpha-stat and pH-stat conditions. RESULTS: CMRO2 did not differ between alpha-stat and pH-stat conditions (1.4 +/- 0.3 ml.100 g-1.min-1; median +/- quartile deviation), and was independent of order of determination. Changes in CBF between alpha-stat and pH-stat conditions were associated with proportional opposite changes in cerebral oxygen extraction. Cerebral blood flow was significantly greater with pH-stat management than with alpha-stat management (37 +/- 5 vs. 30 +/- 3 ml.100 g-1.min-1, respectively). The CBF response to changing PaCO2 was significantly greater when going from alpha-stat to pH-stat conditions (group 1) than in the reverse order (group 2). CONCLUSIONS: During cardiopulmonary bypass at 27 degrees C, hypothermic acid-base management has no measurable effect on CMRO2. CMRO2 was neither extraction limited nor dependent on either PaCO2, CBF, or hemoglobin oxygen affinity differences between alpha-stat and pH-stat management. Cerebral blood flow responses to changing CMRO2 depend on the "starting" conditions, with alpha-stat management appearing to better preserve CBF reactivity than pH-stat management.

Acid-Base Equilibrium↗

PubMed1992

Analysis of vagally induced sinus arrhythmias.

Vagal stimulation at precise times in successive cardiac cycles can elicit sinus arrhythmias. Two mechanisms have been identified that can, but do not necessarily, cause these vagally induced sinus arrhythmias. First, changes in cycle length elicited by a given concentration of acetylcholine (ACh) depend on the phase of the pacemaker cell action potential when the ACh binds to muscarinic receptors. Second, acetylcholinesterase degrades ACh rapidly enough for the mean concentration of ACh per cardiac cycle to vary from cycle to cycle. We used a mathematical model of the underlying cellular physiology, to examine whether these mechanisms are responsible for arrhythmogenesis. Computer simulation showed that both mechanisms contribute to the vagally induced sinus arrhythmias.

Arrhythmias, Cardiac↗

PubMed1992

Brain blood flow and metabolism do not decrease at stable brain temperature during cardiopulmonary bypass in rabbits.

Cerebral blood flow (CBF) during human hypothermic cardiopulmonary bypass has been reported to decrease with time, suggesting that progressive cerebral vasoconstriction or embolic obstruction may occur. We tested the hypotheses: 1) that observed CBF reductions were due to continued undetected brain cooling and 2) that CBF during cardiopulmonary bypass would be stable after achievement of constant brain temperature. Anesthetized New Zealand White rabbits underwent cardiopulmonary bypass (membrane oxygenator, centrifugal pump, bifemoral arterial perfusion) and were assigned to one of three bypass management groups based on perfusate temperature and PaCO2 management: group 1 (37 degrees C, n = 8); group 2 (27 degrees C, pH-stat, n = 9); and group 3 (27 degrees C, alpha-stat, n = 8). Systemic hemodynamics, and cerebral cortical, esophageal, and arterial perfusate temperatures were recorded every 10 min for the first hour of bypass and again at 90 min. CBF and masseter blood flow (radiolabeled microspheres) were determined at 30, 60, and 90 min of bypass, while the cerebral metabolic rate for oxygen (CMRO2) was determined at 60 and 90 min. Groups were comparable with respect to mean arterial pressure, central venous pressure, hematocrit, and arterial oxygen content throughout bypass. Cortical temperature was stable in normothermic (group 1) animals, and there was no significant change in CBF between 30 and 90 min of bypass: 68 +/- 18 versus 73 +/- 20 ml.100 g-1.min-1 (mean +/- SD). In the hypothermic groups (2 and 3), cortical temperature equilibration (95% of the total change) required 41 +/- 6 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Central nervous system toxicity of local anesthetic mixtures in the rat.

Local anesthetics are often administered as mixtures during regional anesthesia. This study investigated whether a synergistic or antagonistic interaction between amide/amide or amide/ester local anesthetic combinations is present with respect to central nervous system toxicity. For surgical preparation, rats were anesthetized with 0.8% halothane in 30% O2/balance N2O and mechanically ventilated. Mean arterial blood pressure and the electroencephalogram were continuously monitored. After surgery, the halothane was discontinued for 15 min. An intravenous infusion of solutions containing lidocaine alone, bupivacaine alone, or any of three mixtures of the two drugs was then begun and continued at a fixed rate until seizure activity was observed on the electroencephalogram. Total administered doses of both drugs were compared by isobolographic analysis. After a similar protocol, a second experiment was performed evaluating lidocaine, tetracaine, or any of three mixtures of those two drugs. In both experiments, normocapnia, normoxia, and normothermia were maintained for all rats. For mixtures of lidocaine/bupivacaine (P = 0.40) and lidocaine/tetracaine (P = 0.24), there was no evidence that a significant degree of either synergism or antagonism was present. At the onset of seizures, mean arterial pressure was lowest in the lidocaine-alone groups in both experiments. Increasing doses of either bupivacaine or tetracaine (with correspondingly decreasing doses of lidocaine) were associated with greater mean arterial pressure values at onset of seizures. We conclude that central nervous system toxic effects of amide/amide or amide/ester anesthetic combinations, such as might occur during accidental intravascular injection, are no more than when the drugs are administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics, Local↗

PubMed1991

Mathematical model of cellular basis for the respiratory sinus arrhythmia.

The respiratory sinus arrhythmia (RSA) is a vagally mediated oscillation in cardiac cycle length at the frequency of breathing. We developed a mathematical model that predicted the temporal and frequency dependence of the RSA. We used the mathematical model to examine the underlying cellular basis for the RSA at the level of the sinus node. We alternated efferent vagal activity between a low and a high frequency at the frequency of breathing. This oscillation caused the rate of acetylcholine (ACh) release to oscillate between a low and a high rate at the frequency of breathing. ACh degradation followed linear pharmacokinetics for physiological concentrations of ACh. Therefore, the concentration of ACh in neuroeffector junctions of the sinus node oscillated at the frequency of breathing. Membrane potential responded rapidly to changes in the concentration of ACh relative to the rate of ACh degradation. Thus, the time course of the RSA depended on the rate of ACh degradation. Membrane potential oscillated at several integer multiples of frequency of breathing and at various higher frequencies, which were integer multiples of the frequency of breathing and the frequencies of firing of the sinus node. However, computing cardiac cycle length from membrane potential eliminated the higher frequencies. Therefore, cardiac cycle length oscillated at several integer multiples of the frequency of breathing, but not at these higher frequencies.

Acetylcholine↗

PubMed1991

Cerebral blood flow response to PaCO2 during hypothermic cardiopulmonary bypass in rabbits.

Differences in cerebral blood flow (CBF) between alpha-stat and pH-stat management depend on preserved responsiveness of the cerebral vasculature to changes in arterial carbon dioxide tension (PaCO2). We tested the hypothesis that hypothermia-induced reductions in CBF would decrease the CBF response to changing PaCO2 (delta CBF/delta PaCO2). Anesthetized New Zealand white rabbits were randomly assigned to one of three temperature groups--group 1 (37 degrees C, n = 9); group 2 (31 degrees C, n = 10); or group 3 (25 degrees C, n = 10)--and were cooled using cardiopulmonary bypass. After esophageal temperature equilibration (approximately 40 min), oxygenator gas flows were serially varied to achieve PaCO2 values of 20, 40, and 60 mm Hg (temperature-corrected). All animals were studied at all three PaCO2 levels in random order. At each level of PaCO2, CBF and masseter blood flow were determined using radiolabeled microspheres. There were no significant differences between groups with respect to mean arterial pressure (approximately 80 mmHg), central venous pressure (approximately 4 mmHg), or hematocrit (approximately 22%). Prior normothermic studies have found delta CBF/delta PaCO2 to be proportional to CBF. Nevertheless, in this study, with hypothermia-induced reductions in CBF, delta CBF/delta PaCO2 was not significantly different between temperature groups. Thus, hypothermia either increased the sensitivity of the cerebral vasculature to carbon dioxide and/or increased the effective level of cerebrospinal fluid respiratory acidosis produced by each increment of temperature-corrected PaCO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Simulation of the diffusion of acetylcholine in the neuroeffector junctions of the sinus node.

Traditionally, the diffusion of acetylcholine (ACh) from a neuron to cardiac muscle in a neuroeffector junction has been modeled as radial diffusion from a nerve ending into a spherical homogeneous medium. Various microscopic structures in the heart may or may not influence the spatial distribution of ACh within neuroeffector junctions. To determine the effect of microscopic anatomy on the diffusion of ACh in neuroeffector junctions, we simulated the diffusion of ACh in a two-dimensional inhomogeneous geometry that was based on micrographs of neuroeffector junctions in the sinus node. ACh was released at sites adjacent to a neuron. Simulations showed that the times of peak concentration after release and the peak concentrations per se were distributed symmetrically above and below and to the right and left of the neuron, but not radially about the neuron. We conclude that the diffusion of ACh in the neuroeffector junctions of the sinus node cannot be predicted well by a mathematical model that assumes radial diffusion in a spherical and homogeneous medium.

Acetylcholine↗

PubMed1989

Mathematical model of dependence of heart rate on tissue concentration of acetylcholine.

The change in sinus period elicited by vagal stimulation depends on the rate of acetylcholine (ACh) release from the nerve endings, the rate of ACh degradation in the nodal tissue, and the responsiveness of the sinus node to ACh. Vagal stimulation in anesthetized dogs prolonged sinus period. After cessation of vagal stimulation, the sinus period returned to the prestimulation period. We developed a mathematical model to analyze the dynamics of ACh degradation in the neuroeffector junction and the dependence of sinus period on the concentration of ACh. From the in vitro reaction kinetics of acetylcholinesterase, we derived an analytical expression for the rate of ACh degradation in the intact animal. Our model represents the electrical behavior of the sinus node by the electrical activity of one pacemaker cell with six membrane ionic currents. This model predicts the decline in sinus period of the intact anesthetized dog as acetylcholinesterase degrades ACh in the neuroeffector junction. The half-life of ACh after cessation of vagal stimulation was estimated to be 2.7 s. We conclude that following termination of vagal stimulation, the sinus node of the intact animal responds to ACh as if the sinus node were one oscillator.

Acetylcholine↗