Action of nicotine on identified cells of the snail brain

Summary Evidence is presented to show that nicotine causes desensitization of certain cells of the snail brain. On cholinoceptive cells where the action of nicotine was excitatory (D-cells), nicotine (10^–6 to 10^–5 M) caused a dose-dependent depolarization and a decrease in input resistance. Firing rate was increased in pacemaker cells. On cholinoceptive cells where the action of nicotine was inhibitory (H-cells), nicotine (10^–6 to 10^–5 M) caused a dose-dependent hyperpolarization and a decrease in input resistance. Firing rate was decreased in pacemaker cells.Both the excitatory and inhibitory effects of nicotine were blocked by d-tubocurarine (10^–5 to 10^–4 M) or atropine (10^–5 to 10^–4 M). Hexamethonium (10^–3 M) reduced the response to nicotine on D-cells but not on H-cells.The membrane potential of both D- and H-type cells returned to control in the presence of nicotine. The duration of the nicotine-induced depolarization of cell V7 was 15±0.8 min (n=10). The duration of the hyperpolarization of cell V5 was 5±0.7 min (n=4). The duration of the nicotine-induced hyperpolarization of H cells was consistently shorter than the duration of the nicotine-induced depolarization of D cells. The time course of changes in input resistance and firing rate paralleled the time course of changes in membrane potential in both cell types.The duration of the nicotine-induced change in membrane potential, input resistance of firing rate was not related to the concentration of nicotine. Similarly, the duration of the depolarization caused by acetylcholine, carbachol, lobeline or DMPP was not related to the drug concentration.At the time of repolarization after nicotine, the application of a second dose of nicotine had no effect or caused a depolarization that was low in amplitude and brief in duration. d-Tubocurarine (10^–6 to 10^–5 M) reduced the amplitude of the nicotine-induced change in membrane potential but did not affect the duration.Increasing the extracellular calcium concentration from 7 mM to 14 mM decreased the duration of the nicotine-induced changes. Also, increasing the pH from 8.0 to 10.0 decreased the duration.Elevating the extracellular magnesium concentration from 4 mM to 20 mM blocked spontaneous e.p.s.p.'s, i.p.s.p.'s and prevented orthodromic stimulation. In elevated magnesium, nicotine caused a depolarization-repolarization sequence similar to that in normal maguesium. It differed in that the amplitude of the depolarization was decreased and the duration increased.The results indicate that the cholinergic receptors of snail neurons closely resemble the cholinergic receptors of frog sartorius muscle.This study was supported by a grant from the American Medical Association Education and Research Foundation.     

Can clinical signs identify newborns with neuromuscular disorders?

OBJECTIVE: To evaluate retrospectively the prevalence of neuromuscular disorders in 83 newborns referred to a tertiary care center because of hypotonia and weakness and/or contractures, with a possible diagnosis of neuromuscular disorder. We also aimed to establish whether clinical signs could help to identify infants with neuromuscular disorders. STUDY DESIGN: Sixty-six of the 83 infants who fulfilled the inclusion criteria (79.5%) had an identifiable disorder, which was a neuromuscular disorder in 39 (46.9%). RESULTS: Absent or extremely reduced antigravity movements were mainly found in infants with neuromuscular disorders (sensitivity and specificity 97.4% and 75%), whereas partial range antigravity movements were more frequent in infants with other diagnosis. Contractures were mainly found in infants with peripheral nerve or muscle involvement but also were relatively frequent in infants with genetic or metabolic syndromes (sensitivity 69.2%, specificity 61.3%). Reduced fetal movements and abnormal liquor were frequent but not present consistently in infants with neuromuscular disorders (sensitivity 46.1% and 38.4%) and were found rarely in infants with other disorders (specificity 88.6% and 75.0%). CONCLUSIONS: Severe muscle weakness and contractures are the most reliable indicators of a neuromuscular disorder and should be carefully assessed in an infant with neonatal hypotonia.     

How does lobeline injected intravenously produce a cough?

In order to examine, whether the lobeline-induced cough is a true reflex or a voluntary effort to get rid of its irritating sensations in the upper respiratory tract, we systematically studied the cough response to lobeline, of subjects who were unable to make conscious discriminations i.e. were either comatose (n=4) or anaesthetized (n=5). 8 microg/kg lobeline injected into the right atrium of one and 29 microg/kg intravenously (i.v.) into another evenly and spontaneously breathing comatose subject produced a cough after 4s and 12s, respectively. Cough was repeatable and showed a dose response relationship i.e., its latency decreasing and its duration/intensity increasing with the dose. In a third subject, capable only of weak spontaneous respiration, a relatively high dose injected into the right atrium (44 microg/kg) generated a pronounced cough-like respiratory movement superimposed on the artificial ventilation and also during the apnoea after disconnecting the pump. No respiratory response was evoked in a fourth subject who had no evidence of brainstem reflexes. In five normals, cough was elicited with a mean dose of 35+/-5 microg/kg i.v. (latency 14+/-2 s; duration 10+/-3 s). After thiopental anaesthesia, injecting 41+/-7 microg/kg produced a cough within 13+/-2 s that lasted for 12+/-2 s. It may be noted that neither the later dose nor the latency or duration of cough that it produced were significantly different from the pre anaesthesia values (P>0.05). These two sets of results show unequivocally that the lobeline-induced cough is evoked reflexly; its magnitude in the conscious state could vary by subjective influences. We discuss the likelihood of its origin from juxtapulmonary capillary receptors.     

Norepinephrine release in medial amygdala facilitates activation of the hypothalamic-pituitary-adrenal axis in response to acute immobilisation stress

Activation of the brain noradrenergic system during stress plays an important integrative function in coping and stress adaptation by facilitating transmission in many brain regions involved in regulating behavioural and physiological components of the stress response. The medial amygdala (MeA) has been implicated in modulation of stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, and MeA is a target of innervation from brainstem noradrenergic neurones. However, it is not known whether, and to what extent, activation of the ascending noradrenergic innervation of MeA might modulate stress-induced adrenocorticotropic hormone (ACTH) secretion. In the first experiment in this study, we measured extracellular norepinephrine (NE) levels in MeA using in vivo microdialysis. The concentration of NE in dialysate samples collected in MeA was elevated by more than three-fold over baseline in response to acute immobilisation stress, providing evidence of a possible modulatory role for NE in the MeA during stress. This potential role was then assessed in the second experiment by measuring changes in the elevation of plasma ACTH concentration induced by acute immobilisation stress immediately following bilateral microinjections of alpha1- or beta-adrenergic receptor antagonists directly into MeA. Compared to vehicle-injected controls, the alpha1-receptor antagonist benoxathian dose-dependently and significantly attenuated the ACTH response to acute stress, whereas combined beta1/beta2-receptor blockade in MeA had only a modest effect. These results indicate that MeA does play a role in the stress response, and support the hypothesis that stress-induced activation of NE release in MeA, acting primarily through alpha1 receptors, facilitates activation of the HPA axis in response to acute stress.     

Increased dietary sodium enhances activation of neurons in the medullary cardiovascular pathway during acute sodium loading in the rat

Increased sodium ingestion diminishes baroreflex-induced bradycardia in animals during acute sodium loading. These experiments studied effects of high sodium diet on activation of central nervous system sites associated with baroreflex activation and cardiovascular responses to hypernatremia during systemic sodium administration. Fos-like (Fos-Li) protein immunoreactivity was measured to estimate activation of neurons in the medullary baroreflex pathway (nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM)), and in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) in male Sprague-Dawley rats consuming standard chow and either tap water (TAP) or isotonic saline (ISO) for 2-3 weeks. Fos-Li immunoreactivity in the PVN and SON was similar in rats consuming TAP and ISO infused with 0.6 M NaCl. However, there were significantly more Fos-Li positive cells in NTS and CVLM of animals consuming ISO and infused with 0.6 M NaCl than any other experimental group, while Fos-Li immunoreactivity was similar in the RVLM in all animals. In conclusion, these data demonstrate that activation of neurons in the NTS and CVLM was significantly enhanced by moderate sodium loading in animals consuming high dietary sodium. The increased basal activation of neurons in these medullary sites could account for decreased baroreflex-induced bradycardia observed during ingestion of a high salt diet and acute, moderate sodium loading.     

Home nocturnal hemodialysis in children

OBJECTIVE: To describe the effect of home nocturnal hemodialysis (NHD) in North American children. STUDY DESIGN: Four teenagers underwent NHD for 8 hours, 6 to 7 nights/week, using either central venous lines or fistulae for periods of 6 to 12 months. Blood flow approximated 200 mL/min, and dialysate flow was 300 mL/min; the dialysate contained potassium and phosphate. The procedure was remotely monitored. RESULTS: The children had unrestricted diets and fluid allowance and did not require phosphate binders. Persistent relative hypotension developed in 2 of 4 children. Weekly Kt/V urea values were consistently >10; other biochemical measures varied. Quality of life and school attendance improved in 3 of 4 children. The workload and reported emotional burden of NHD was substantial. No significant complications occurred. Dialysate losses of calcium, phosphate and carnitine required supplementation. The annual cost per patient was dollar 64,000 Canadian, which represented a 27% savings compared with thrice weekly in-center hemodialysis. CONCLUSIONS: NHD is feasible in selected children, allows free dietary and fluid intake, and improves patient wellbeing. The burden on the family is substantial, and NHD requires support of a dedicated multidisciplinary team.     

Milrinone and Low Cardiac Output Following Cardiac Surgery in Infants: Is There a Direct Myocardial Effect?

We assessed the effect of milrinone on myocardial function in pediatric patients with postoperative low cardiac output syndrome by index of myocardial performance in a prospective, open-label, nonrandomized, consecutive study. Fifteen patients with low cardiac output syndrome following cardiac surgical treatment were studied in the tertiary cardiothoracic pediatric intensive care unit between April 2001 and November 2003 (age range, 0.2–16 months; median, 7; weight, 2.7–11.8 kg; median, 5). Echocardiographic, Doppler-derived, time interval-based index of myocardial performance (Tei index) was used to study cardiac function prior to and while on intravenous milrinone treatment for 18–24 hours. Treatment with milrinone led to improvement in biventricular myocardial function [mean right ventricular index from 0.521 (SD-0.213) to 0.385 (SD-0.215), p = 0.003; mean left ventricular index from 0.636 (SD-0.209) to 0.5 (SD-0.171), p = 0.012). No difference was found in the values of heart rate corrected right or left ventricular ejection time prior to and while on treatment with milrinone (right ventricle: mean, 1.23 (SD-0.42) and 1.14 (SD-0.48), p = 0.29; left ventricles: mean, 1.17 (SD-0.51) and 1.13 (SD-0.48), p = 0.66) Our data support the direct myocardial effect of milrinone as part of the mechanism behind its already proven benefit in children with low cardiac output syndrome following cardiac surgery.     

Caudal anesthesia for vascular access procedures in two extremely small premature neonates

With advances in neonatology, there is an increasing need for central vascular access in extremely small (<1,000 g) premature infants. Although the use of peripherally inserted central venous lines have become common practice, surgeons still frequently perform central venous line placements via cut-down in difficult access patients. The advantages of general anesthesia for vascular access procedures are obvious for optimal pain control and ideal operative exposure; however, extremely premature infants are at significant risk for prolonged endotracheal intubation with postoperative apneas. We report two cases where regional caudal anesthesia with bupivacaine and clonidine without intubation was successfully utilized at bedside during central venous line placements in premature infants weighing <600 g. The operative field was ideal with adequate motor and sensory block with caudal anesthesia and both infants received only oxygen by nasal cannula.