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This essay addresses the recent deceleration in the pace of global FDI and asks whether multinational corporations are actually in retreat. It identifies the forces that are slowing the expansion of FDI, and sketches the role that multinational corporations will play in the future.

Research background: The authors are providing an update to the ongoing process of Brexit and the negotiations between the UK and the EU, following their own previous research in this area. Purpose of the article: In 2019, the aviation sector in the UK ranked as the third largest in the world. London Heathrow, a hub to many UK airlines, ranked as Europe’s busiest airport and seventh busiest in the world. [1] Brexit negotiations between the UK and the EU, in the context of globalization and the existing deep ties within the EU institutions, presents a complex task. Following the Brexit referendum in June 2016, where the majority of the electorate decided that Britain should leave the EU, events have progressed significantly by the UK leaving the EU formally at 23:59 on the 31st January 2020. However, negotiations are still ongoing and when it comes to Aviation, the outcome in many key areas is still uncertain. Methods: The article is based on data and information collation as well as the authors’ experience within the industry. Findings & Value added: Once the transition period terminates on the 31st December 2020, Brexit will have a significant influence on trading in the European domestic market and globally on the international market. This paper discusses available options for the UK and the EU that follow from existing decisions in the Brexit bill, as well as outlining possible future developments. Furthermore, in light of the existing threats to the Aviation industry from the ongoing COVID-19 pandemic and the cessation of air travel for many weeks, adjustments to the Brexit plan might be required.

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase. [ABSTRACT FROM AUTHOR]

Enalapril is the result of a targeted research programme to develop a non-mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. Over 3500 patients world-wide have received enalapril or enalaprilat. Long-term experience at present includes over 2500 patients. While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril-type side-effects, particularly the skin rash, taste loss, leukopenia and proteinuria. Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension. [ABSTRACT FROM AUTHOR]

This paper gives an overview of a combined experimental-numerical study on vascular self-healing (SH) systems for cementitious composite materials. The work aimed to bridge the gap between numerical and experimental investigations for this type of SH system and to provide a set of data for developing, calibrating and validating a finite element model for these materials. The study investigated both healing-agent transport and mechanical damage-healing processes, including healing-agent curing. The experimental programme included mechanical tests on notched concrete beams and compact direct-tension specimens with inbuilt vascular healing systems, as well as tests to measure the transport properties of healing-agent within discrete concrete cracks and through the concrete matrix. The new coupled model employs elements with embedded strong discontinuities to simulate cracks and mechanical healing behaviour. A damage-healing constitutive model is described that simulates multiple damage-healing ‘events’. This mechanical model is coupled to discrete and continuum flow models that simulate healing-agent transport. The transport model accounts for pressurised and capillary flow, as well as curing-dependent flow properties. The main focus of this contribution is to show how these parallel programmes of work were combined so that the experimental observations guided the numerical developments and modelling questions were answered using experimental findings.

The aim of the study was to determine the physical properties of gbafi lo fruit and kernel, namely, axial dimension, geometrical and arithmetic mean diameter, sphericity, aspect ratio, 1000 unit mass, surface area, true and bulk density, porosity angle of repose and coeffi cient of static friction. Investigation of physical properties of gbafi lo (Chrysobalanus icaco) is important for the design of appropriate equipment for processing, transporting, cleaning, sorting, packaging and storage processes. The mean length, width and thickness of gbafi lo fruit (Chrysobalanus icaco) were determined at 8.3% moisture content (d.b.). The analysis of variance showed that variations in the values obtained for fruit and kernel for axial dimensions were signifi cantly different at 5% probability level. The arithmetic and geometric mean diameter for gbafi lo fruit were 24.95 mm and 24.74 mm. The sphericity, surface area and as well as 1 000 unit mass of gbafi lo kernel were 0.82, 1 056.70 mm2 and 2 804.64 g. True and bulk densities were 989.19 kg/m-3 and 652.53 kg/m-3 for kernel. Angle of static friction of gbafi lo fruit and kernel were 19.34° and 17.61°. Data obtained were subjected to analysis of variance (ANOVA) and Duncan Multiple Range (DMR) using Statistical Analysis System. The static coeffi cient of friction of plywood structural surface was observed to be the highest followed by galvanized steel sheet and glass. This is an indication that plywood interior lining would not be suitable material for chute design. All the gbafi lo fruit and kernel parameters investigated were signifi cantly different (P < 0.05). This fi nding could therefore be useful in the design and fabrication of gbafi lo processing machines.

Abstract Background Outer membrane proteins (OMPs) of Pasteurella multocida have various functions related to virulence and pathogenesis and represent important targets for vaccine development. Various bioinformatic algorithms can predict outer membrane localization and discriminate OMPs by structure or function. The designation of a confident prediction framework by integrating different predictors followed by consensus prediction, results integration and manual confirmation will improve the prediction of the outer membrane proteome. Results In the present study, we used 10 different predictors classified into three groups (subcellular localization, transmembrane β-barrel protein and lipoprotein predictors) to identify putative OMPs from two available P. multocida genomes: those of avian strain Pm70 and porcine non-toxigenic strain 3480. Predicted proteins in each group were filtered by optimized criteria for consensus prediction: at least two positive predictions for the subcellular localization predictors, three for the transmembrane β-barrel protein predictors and one for the lipoprotein predictors. The consensus predicted proteins were integrated from each group into a single list of proteins. We further incorporated a manual confirmation step including a public database search against PubMed and sequence analyses, e.g. sequence and structural homology, conserved motifs/domains, functional prediction, and protein-protein interactions to enhance the confidence of prediction. As a result, we were able to confidently predict 98 putative OMPs from the avian strain genome and 107 OMPs from the porcine strain genome with 83% overlap between the two genomes. Conclusions The bioinformatic framework developed in this study has increased the number of putative OMPs identified in P. multocida and allowed these OMPs to be identified with a higher degree of confidence. Our approach can be applied to investigate the outer membrane proteomes of other Gram-negative bacteria.

Abstract Background Cardiac arrest affects 30-35, 000 hospitalised patients in the UK every year. For these patients to be given the best chance of survival, high quality cardiopulmonary resuscitation (CPR) must be delivered, however the quality of CPR in real-life is often suboptimal. CPR feedback devices have been shown to improve CPR quality in the pre-hospital setting and post-event debriefing can improve adherence to guidelines and CPR quality. However, the evidence for use of these improvement methods in hospital remains unclear. The CPR quality improvement initiative is a prospective cohort study of the Q-CPR real-time feedback device combined with post-event debriefing in hospitalised adult patients who sustain a cardiac arrest. Methods/design The primary objective of this trial is to assess whether a CPR quality improvement initiative will improve rate of return of sustained spontaneous circulation in in-hospital-cardiac-arrest patients. The study is set in one NHS trust operating three hospital sites. Secondary objectives will evaluate: any return of spontaneous circulation; survival to hospital discharge and patient cerebral performance category at discharge; quality of CPR variables and cardiac arrest team factors. Methods: All three sites will have an initial control phase before any improvements are implemented; site 1 will implement audiovisual feedback combined with post event debriefing, site 2 will implement audiovisual feedback only and site 3 will remain as a control site to measure any changes in outcome due to any other trust-wide changes in resuscitation practice. All adult patients sustaining a cardiac arrest and receiving resuscitation from the hospital cardiac arrest team will be included. Patients will be excluded if; they have a Do-not-attempt resuscitation order written and documented in their medical records, the cardiac arrest is not attended by a resuscitation team, the arrest occurs out-of-hospital or the patient has previously participated in this study. The trial will recruit a total of 912 patients from the three hospital sites. Conclusion This trial will evaluate patient and process focussed outcomes following the implementation of a CPR quality improvement initiative using real-time audiovisual feedback and post event debriefing. Trial registration ISRCTN56583860

Abstract Background The role of the innate immune protein mannose-binding lectin (MBL) in host defence against severe respiratory infection remains controversial. Thoracic empyema is a suppurative lung infection that arises as a major complication of pneumonia and is associated with a significant mortality. Although the pathogenesis of thoracic empyema is poorly understood, genetic susceptibility loci for this condition have recently been identified. The possible role of MBL genotypic deficiency in susceptibility to thoracic empyema has not previously been reported. Methods To investigate this further we compared the frequencies of the six functional MBL polymorphisms in 170 European individuals with thoracic empyema and 225 healthy control individuals. Results No overall association was observed between MBL genotypic deficiency and susceptibility to thoracic empyema (2 × 2 Chi square = 0.02, P = 0.87). Furthermore, no association was seen between MBL deficiency and susceptibility to the Gram-positive or pneumococcal empyema subgroups. MBL genotypic deficiency did not associate with progression to death or requirement for surgery. Conclusions Our results suggest that MBL genotypic deficiency does not associate with susceptibility to thoracic empyema in humans.

Abstract Background The Mannheimia species encompass a wide variety of bacterial lifestyles, including opportunistic pathogens and commensals of the ruminant respiratory tract, commensals of the ovine rumen, and pathogens of the ruminant integument. Here we present a scenario for the evolution of the leukotoxin promoter among representatives of the five species within genus Mannheimia. We also consider how the evolution of the leukotoxin operon fits with the evolution and maintenance of virulence. Results The alignment of the intergenic regions upstream of the leukotoxin genes showed significant sequence and positional conservation over a 225-bp stretch immediately proximal to the transcriptional start site of the lktC gene among all Mannheimia strains. However, in the course of the Mannheimia genome evolution, the acquisition of individual noncoding regions upstream of the conserved promoter region has occurred. The rate of evolution estimated branch by branch suggests that the conserved promoter may be affected to different extents by the types of natural selection that potentially operate in regulatory regions. Tandem repeats upstream of the core promoter were confined to M. haemolytica with a strong association between the sequence of the repeat units, the number of repeat units per promoter, and the phylogenetic history of this species. Conclusion The mode of evolution of the intergenic regions upstream of the leukotoxin genes appears to be highly dependent on the lifestyle of the bacterium. Transition from avirulence to virulence has occurred at least once in M. haemolytica with some evolutionary success of bovine serotype A1/A6 strains. Our analysis suggests that changes in cis-regulatory systems have contributed to the derived virulence phenotype by allowing phase-variable expression of the leukotoxin protein. We propose models for how phase shifting and the associated virulence could facilitate transmission to the nasopharynx of new hosts.

This paper describes the implementation of INFIBRA, a machine vision system used in the quality control of acrylic fibre production. The system was developed by INETI under a contract with a leading industrial manufacturer of acrylic fibres. It monitors several parameters of the acrylic production process. This paper presents, after a brief overview of the system, a detailed description of the machine vision algorithms developed to perform the inspection tasks unique to this system. Some of the results of online operation are also presented.

When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α(2)-adrenergic agonist clonidine (20-40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5-5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5 neurons.

Background: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic-intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements., Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt., Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group., Conclusion: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia.

Recently, we reported that the suppression of hypoglossal (XII) motoneuronal activity that occurs during the carbachol-induced, rapid eye movement (REM) sleep-like state is abolished by the microinjection into the XII nucleus of a drug mix that antagonizes aminergic excitation and amino acid-mediated inhibition (prazosin, methysergide, bicuculline and strychnine). We now assess the role of glycinergic inhibition in the depression of XII motoneuronal activity and estimate the distribution of the antagonists around the XII nucleus at the time when they are effective. Towards the first goal, REM sleep-like episodes were elicited in urethane-anesthetized rats by 10 nl carbachol microinjections into the dorsomedial pons prior to, and at different times after, combined microinjections into the XII nucleus of only three antagonists (strychnine omitted). As in our previous study, the carbachol-induced depression of XII activity was abolished during tests performed 42-88 min after the antagonists, whereas other characteristic effects of carbachol (appearance of hippocampal theta, cortical activation, decreased respiratory rate) remained intact. The depressant effect of carbachol on XII motoneurons partially recovered after 2.5 h. Towards the second goal, using a drug diffusion model, we determined that the tissue concentrations of the antagonists at the time when they were effective were within the range of their selective actions, and the drugs acted within 0.9-1.4 mm from the injection sites, thus within a space containing XII motoneurons and their dendrites. We conclude that antagonism of alpha-adrenergic, serotonergic, and GABA(A) receptors are sufficient to abolish the REM sleep-like atonia of XII motoneurons.

Rationale: Studies of hypoglossal (XII) motoneurons that innervate the genioglossus muscle, an upper airway dilator, suggested that the suppression of upper airway motor tone during REM sleep is caused by withdrawal of excitation mediated by norepinephrine and serotonin., Objectives: Our objectives were to determine whether antagonism of aminergic receptors located in the XII nucleus region can abolish the REM sleep-like atonia of XII motoneurons, and whether both serotonergic and noradrenergic antagonists are required to achieve this effect., Methods: REM sleep-like episodes were elicited in anesthetized rats by pontine carbachol injections before and at various times after microinjection of prazosin and methysergide combined, or of only one of the drugs, into the XII nucleus., Measurements and Main Results: Spontaneous XII nerve activity was significantly reduced, by 35 to 81%, by each antagonist alone and in combination, indicating that XII motoneurons were under both noradrenergic and serotonergic endogenous excitatory drives. During the 32 to 81 min after microinjections of both antagonists, pontine carbachol caused no depression of XII nerve activity, whereas other characteristic effects (activation of the hippocampal and cortical EEG, and slowing of the respiratory rate) remained intact. A partial recovery of the depressant effect of carbachol then occurred parallel to the recovery of spontaneous XII nerve activity from the depressant effect of the antagonists. Microinjections of either antagonist alone did not eliminate the depressant effect of carbachol., Conclusions: The REM sleep-like depression of XII motoneuronal activity induced by pontine carbachol can be fully accounted for by the combined withdrawal of noradrenergic and serotonergic effects on XII motoneurons., Competing Interests: Statement : V.B.F. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. R.O.D. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. L.K. acted as a one-time consultant for the following commercial entities interested in pharmacologic treatments for the obstructive sleep apnea syndrome for which he received honoraria not exceeding $2,500 per any one instance: Hypnion, Sepracor, and Cypress Bioscience.

Study Objectives: Two pontine reticular regions are implicated in cholinergic triggering of rapid eye movement (REM) sleep: the dorsomedial tegmental region and the ventral nucleus pontis oralis. We previously determined that, in urethane-anesthetized rats, microinjections of a cholinergic agonist, carbachol, into the dorsal region produce REM sleep-like effects comprising cortical activation, hippocampal theta rhythm, suppression of hypoglossal (XII) nerve activity, and silencing of pontine noradrenergic neurons. Our goal was to determine whether carbachol injections into the ventral nucleus pontis oralis elicits comparable effects., Design: Recording of cortical electroencephalogram, hippocampal activity, XII nerve activity, and discharge of noradrenergic cells of the locus coeruleus., Setting: Basic neurophysiologic research laboratory., Participants and Interventions: Urethane-anesthetized, paralyzed, and artificially ventilated or nonparalyzed and spontaneously breathing rats with microinjections of carbachol (10 nL, 10 mM) into the ventral nucleus pontis oralis., Measurements and Results: In artificially ventilated rats, carbachol injections repeatedly elicited cortical activation and hippocampal theta rhythm. Concomitantly, the activity of locus coeruleus neurons increased from 2.0 per second +/- 0.4 (SE) to 2.6 per second +/- 0.4 (P < .05, n = 8), as did XII nerve activity (by 42.5% +/- 8.8%; P < .01). In spontaneously breathing animals, carbachol similarly activated the cortical electroencephalogram and hippocampal activity, whereas XII nerve activity was reduced by 6.7% +/- 2.5% (P < .05) together with increased ventilation, as indicated by reduced end-expiratory CO2., Conclusion: Carbachol injections into the ventral nucleus pontis oralis activate, rather than silence, noradrenergic locus coeruleus neurons. This is not compatible with the state of REM sleep.

It is hypothesized that the suppression of motor activity (atonia) that occurs during REM sleep is caused by the combined inhibition of motoneurons by glycine or GABA and withdrawal of excitation mediated by serotonin and norepinephrine. However, it is not known whether these mechanisms can fully account for the atonia. In urethane-anesthetized, paralyzed and artificially ventilated rats, REM sleep-like episodes can be repeatedly elicited by microinjections of a cholinergic agonist, carbachol, into the dorsomedial pons. We used this model to determine whether microinjections of a combination of antagonists of serotonergic, adrenergic, GABA(A) and glycinergic receptors (methysergide, prazosin, bicuculline and strychnine) into the XII nucleus can abolish the carbachol-induced depression of XII motoneuronal activity. REM sleep-like episodes were elicited prior to, and at different times after, antagonist microinjections. In all six rats studied, the depression of XII motoneuronal activity did not occur when tested 30-60 min after the antagonists, whereas other characteristic features of the response (latency, duration, the appearance of hippocampal theta rhythm, activation of the cortical EEG, slowing of the respiratory rate) remained intact. The carbachol-induced depression partially recovered after 2-3 hours. We conclude that the REM sleep-like depression of XII motoneuronal activity can be fully accounted for by all or some of the following mechanisms: a withdrawal of motoneuronal excitation mediated by norepinephrine and serotonin and increased inhibition mediated by GABA and glycine.

The A5 noradrenergic neurons are considered important for cardiorespiratory regulation. We hypothesized that A5 cells are silenced during rapid eye movement (REM) sleep, thereby contributing to cardiorespiratory changes and suppression of hypoglossal (XII) motoneuronal activity. We used an anesthetized, paralyzed, and artificially ventilated rat in which pontine microinjections of carbachol trigger signs of REM sleep, including hippocampal theta rhythm, motor suppression, and silencing of locus coeruleus neurons. All 16 putative noradrenergic A5 cells recorded were strongly suppressed when the REM sleep-like episodes were elicited and also after intravenous clonidine. Antidromic mapping showed that none of six neurons tested projected to the XII nucleus, whereas three of five projected to the nucleus of the solitary tract and two of four to the rostral ventrolateral medulla. Bilateral microinjections of clonidine into the A5 regions did not alter XII nerve activity. These data suggest that A5 neurons are silenced during natural REM sleep. This will lead to decreased norepinephrine release and may alter synaptic transmission in the nucleus of the solitary tract and rostral ventrolateral medulla without, however, a detectable impact on XII motoneurons.

In individuals with compromised upper airway anatomy, genioglossus (GG), the main protruder muscle of the tongue, is an important upper airway dilator which helps prevent upper airway obstructions. During rapid eye movement (REM) sleep, both the tonic and inspiratory-modulated components of GG activity are suppressed in parallel with the characteristic postural atonia. We tested whether the REM sleep-related reduction in the respiratory activity of GG may, in part, result from a reduced inspiratory drive relayed to hypoglossal (XII) motoneurons from their premotor medullary inspiratory neurons. In 15 urethane-anesthetized, paralyzed, vagotomized and artificially ventilated rats, we recorded XII nerve activity and the extracellular activity of medullary inspiratory-modulated neurons antidromically activated with latencies of 0.8 ms +/- 0.3(SD) from within (n = 19) or adjacent to (n = 11) the XII nucleus. Carbachol (10-20 nl, 10 mM), a cholinergic agonist, was microinjected into the dorsomedial pons. Such injections trigger a REM sleep-like state in chronically instrumented, intact animals and, in anesthetized rats, produce respiratory and electrocortical changes similar to those of REM sleep. Following the injections, the respiratory component of XII nerve activity was depressed by 51 +/- 22%, while the mean inspiratory firing rate of the neurons decreased by only 7.4 +/- 13.8% (from 69 +/- 34 Hz to 65 +/- 37 Hz; P < 0.02; n = 30). The activity of ventral respiratory group (VRG) and reticular formation inspiratory neurons with axons within the XII nucleus was reduced by 10 +/- 14% (P < 0.005; n = 19), whereas the activity of neurons located near the VRG that had axons passing below the XII nucleus did not change (n = 5). Thus, the depressant effect of carbachol on medullary inspiratory neurons was slightly more pronounced in reticular formation and VRG cells premotor to XII motoneurons than in other medullary inspiratory cells. For all cells, the magnitude of the decrease of cell activity was not related to the magnitude of depression of XII nerve activity, the simultaneously occurring decrease in respiratory rate or the cell's control firing rate. Since the magnitude of this depressant effect on all cell types was disproportionately small when compared with the depression of XII nerve activity, the REM sleep-like decrease in GG activity must be mainly mediated by non-respiratory premotor pathways.

Microinjections of carbachol into the pontine tegmentum of decerebrate cats have been used to study the mechanisms underlying the suppression of postural and respiratory motoneuronal activity during the resulting rapid eye movement (REM) sleep-like atonia. During REM sleep, distinct respiratory muscles are differentially affected; e.g., the activity of the diaphragm shows little suppression, whereas the activity of some upper airway muscles is quite strong. To determine the pattern of the carbachol-induced changes in the activity of different groups of upper airway motoneurons, we simultaneously recorded the efferent activity of the recurrent laryngeal nerve (RL), pharyngeal branch of the vagus nerve (Phar), and genioglossal branch of the hypoglossal (XII) and phrenic (Phr) nerves in 12 decerebrate, paralyzed, vagotomized, and artificially ventilated cats. Pontine carbachol caused a stereotyped suppression of the spontaneous activity that was significantly larger in Phar expiratory (to 8.3% of control) and XII inspiratory motoneurons (to 15%) than in Phr inspiratory (to 87%), RL inspiratory (to 79%), or RL expiratory motoneurons (to 72%). The suppression in upper airway motor output was significantly greater than the depression caused by a level of hypocapnia that reduced Phr activity as much as carbachol. We conclude that pontine carbachol evokes a stereotyped pattern of suppression of upper airway motor activity. Because carbachol evokes a state having many neurophysiological characteristics similar to those of REM sleep, it is likely that pontine cholinoceptive neurons have similar effects on the activity of upper airway motoneurons during both states.

The loss of tone in upper airway muscles contributes to disorders of breathing during sleep. In an animal model of rapid eye movement sleep atonia, decrements in the activity of upper airway motoneurons are caused by withdrawal of excitation mediated by serotonin and other transmitters, rather than by state-dependent inhibition.

Serotonergic neurons decrease their activity during sleep, especially rapid eye movement sleep, thereby reducing their facilitatory effect on upper airway motoneurons. The magnitude of teh sleep-related loss of tone varies among upper airway muscles (e.g., pharyngeal dilator motoneurons are more suppressed than laryngeal motoneurons). We hypothesized that these differences may be related to the sensitivity of different groups of upper airway motoneurons to serotonin. Experiments were done on decerebrate, vagotomized, paralysed and artificially-ventilated cats. Hypoglossal and laryngeal motoneurons were recorded extracellularly using five-barrel pipettes filled with: serotonin, glutamate and methysergide (serotonergic antagonist) for iontophoresis, and NaCl for recording and current balancing. All but two of the 65 hypoglossal motoneurons (45 inspiratory, 10 expiratory, 10 tonic) and 27 out of 32 laryngeal motoneurons (14 inspiratory, 18 expiratory) were excited by serotonin, and the excitation was abolished by methysergide. To compare the magnitude of the excitatory effect among distinct motoneuronal groups, we applied small ejection currents in a standardized manner (+15 nA for 3 min; 10 mM serotonin in 150 NaCl) onto spontaneously active motoneurons (13 inspiratory hypoglossal, 11 inspiratory laryngeal and 11 expiratory laryngeal). Serotonin increased the number of spikes per respiratory burst of inspiratory hypoglossal motoneurons from 19 +/- 4.0 (S.E.M.) to 35 +/- 4.8, of inspiratory laryngeal motoneurons from 44 +/- 8.3 to 55 +/- 8.8, and of expiratory laryngeal motoneurons from 23 +/- 4.8 to 33 +/- 6.2. The relative increases in activity (to 220% +/- 24, 147% +/- 23 and 148% +/- 9 of control, respectively) were significantly higher in hypoglossal than in laryngeal motoneurons. In addition, the excitatory effect developed significantly faster in hypoglossal than in laryngeal motoneurons. Methysergide reduced the spontaneous activity of about half the hypoglossal and laryngeal motoneurons to 66% +/- 5 of control. Thus, the sensitivity to the excitatory effects of serotonin varies among different pools of upper airway motoneurons. These differences correlate with the pattern of airway muscle hypotonia seen during sleep.

The facilitatory effect of serotonin (5HT) on hypoglossal (XII) motoneurons is likely to be reduced during rapid eye movement (REM) sleep, when the activity of the brainstem serotonergic system reaches its nadir. Therefore, we assessed the hypothesis that application of exogenous 5HT will attenuate the REM sleep-like suppression of XII motoneurons produced in decerebrate cats by pontine microinjections of a cholinergic agonist, carbachol. Microinjections of 5HT or 5-carboxamidotryptamine into the XII nucleus increased XII nerve activity to 182 +/- 53% (standard deviation; SD) of control. Subsequent pontine microinjections of carbachol reduced XII nerve activity by 55 +/- 21% of the pre-5HT level (n = 12). Microinjections of methysergide (a 5HT antagonist) into the XII nucleus reduced XII nerve activity to 54 +/- 17% of the pre-methysergide control (n = 6). Pontine carbachol injections after methysergide further reduced XII nerve activity by 49 +/- 20% of the pre-methysergide level. Treatments with both agonists and the antagonist attenuated the carbachol-induced decrease when compared to two previous studies using the same model: 1) In experiments with no injections of serotonergic agents, pontine carbachol injections decreased XII nerve activity by 90 +/- 6% of control. 2) After enhancement of XII nerve activity by inhibitory amino acid antagonists (to 135 +/- 60%), the subsequent carbachol-induced decrease was even larger, 112 +/- 62% of control. We propose that serotonergic excitation can significantly attenuate the REM sleep-like suppression of XII nerve activity, and that this is achieved, in part, by substituting for the decreased endogenous 5HT in the XII nucleus. The study also demonstrates that other, non-serotonergic, mechanisms also contribute to the carbachol-induced suppression.

1. The activity of most brainstem serotonergic cells is suppressed during sleep, particularly the rapid eye movement (REM) phase. Thus, they may play a major role in state-dependent changes in CNS functioning. Our main goal was to search for medullary raphe cells having axonal branches in the region of the hypoglossal (XII) motor nucleus and assess their behaviour during the atonia produced by microinjections of a cholinergic agonist, carbachol, into the dorsal pontine tegmentum. In chronic animals, such microinjections evoke a desynchronized sleep-like state similar to natural REM sleep; in decerebrate animals, they produce eye movements and a motor suppression similar to the postural atonia of REM sleep. 2. In decerebrate, paralysed, vagotomized and artificially ventilated cats, we recorded extracellularly from medullary raphe cells antidromically activated from the XII nucleus region. Forty-five cells recorded in the raphe obscurus and pallidus nuclei were antidromically activated with latencies characteristic of non-myelinated fibres (4.4-42.0 ms). For thirty-three of the forty-five cells, we found one or more axonal branches within or just below the XII nucleus. The remaining twelve cells, in addition to the XII nucleus, had axonal ramifications in the medial nucleus of the solitary tract (NTS) and/or the dorsal motor nucleus of the vagus (DMV). 3. A subset of fourteen spontaneously active cells with identified axonal projections were held long enough to be recorded during the carbachol-induced atonia, and eight of these also during the subsequent recovery and a systemic administration of the serotonergic 1A receptor agonist (+/-)8-hydroxy-2-(di-N-propylamino)tetrealin hydrobromide (8-OH-DPAT). All but one were suppressed during the atonia in parallel to the suppression of XII, phrenic and postural nerve activities (firing rate, 1.3 +/- 0.7 Hz before and 0.1 +/- 0.2 Hz after carbachol (means +/- S.D.)). Following the recovery from the atonia, the firing rates of the eight cells increased to the pre-carbachol level (1.6 +/- 1.0 Hz). Subsequently, all were silenced by 8-OH-DPAT. 4. These cells fulfil most physiological criteria for serotonergic cells and have the potential to modulate, in a state-dependent manner, activities in the motor XII nucleus, visceral sensory NTS, and DMV. The decrements in serotonergic neuronal activity that occur during the carbachol-induced atonia suggest that a similar withdrawal of serotonergic input may occur during REM sleep and contribute to the characteristic reductions in upper airway motor tone.

The excitability of hypoglossal (XII) motoneurons innervating genioglossal muscles is markedly suppressed during the rapid-eye-movement (REM) stage of sleep. This may contribute to airway obstructions in sleep apnea patients. Based on our earlier studies in decerebrate cats using injections of carbachol into the pons to induce a REM sleep-like atonia and microinjections of serotonin (5HT) into the XII motor nucleus, we hypothesized that a sleep-related withdrawal of the serotonergic excitatory input to XII motoneurons may play a major role in these processes. To test one aspect of this hypothesis, we inserted microdialysis probes into the XII nucleus region of decerebrate, paralyzed, vagotomized and artificially ventilated cats. The probes were perfused without or with the addition of a 5HT reuptake blocker, clomipramine. The levels of 5HT and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined using HPLC and electrochemical detection in dialysate samples collected over successive 20 min periods under four successive experimental conditions: control (at least 2 h after probe insertion); during the postural atonia and respiratory depression produced by pontine microinjection of carbachol; recovery from the effects of carbachol produced by pontine microinjection of atropine; and, to verify that the presence of 5HT in the dialysate was related to the activity of serotonergic cells of the brainstem, following administration of 8-OH-DPAT, a 5HT 1A receptor agonist known to suppress activity in the serotonergic cells of the raphe system. After correcting for recovery rates of individual probes, the mean control 5HT level in the extracellular space of the XII nucleus region was 7.9 +/- 4.4 nM (S.D.) in eight experiments without reuptake blockers. During the carbachol-induced depression, it was reduced to 70 +/- 20% of the pre-carbachol level. It increased to the original control level 98 +/- 27% after pontine injection of atropine. 8-OH-DPAT reduced the 5HT level to 43 +/- 14% of the post-atropine level. Changes in the 5HIAA level were not as consistent as for 5HT and did not reach statistical significance under any of the experimental conditions. Thus, a functionally significant amount of 5HT is present in the extracellular space within the XII nucleus region, and its decrement during carbachol-induced, REM sleep-like atonia is likely to reflect that occurring during natural REM sleep; this may contribute to the decreased tone of upper airway muscles and airway patency.

The safety of sotalol was evaluated in 3,257 patients treated for cardiac arrhythmias in double-blind and open-label clinical trials that support United States registration of the drug. In this composite population, 80% of patients had structural heart disease and 42% had life-threatening ventricular arrhythmias, i.e., ventricular tachycardia (VT) or fibrillation (VF). Proarrhythmia was reported in 141 patients (4.3%). Of these, 78 (2.4%) had torsades de pointes and 26 (0.8%) had sustained VT or VF. The overall incidence was higher in patients treated for sustained VT or VF (6.5%). In these patients, serious proarrhythmia was predominantly torsades de pointes (4.1%) and was more prevalent in patients with congestive heart failure and low ejection fraction. Torsades de pointes was observed early in the course of treatment, and its occurrence was related to dose. The overall mortality in patients treated with sotalol was 4.3% (139 patients); in patients with life-threatening arrhythmias, cardiac mortality was 4.8%. In only 27 patients (0.8%) was the death thought to be potentially drug-related. The deaths were not related to dose. Data from a previously reported placebo-controlled postmyocardial infarction trial indicated no significant difference in mortality between sotalol and placebo. Heart failure was reported in 3.3% of patients and was most prevalent in those with a previous history of congestive heart failure, cardiomyopathy, or structural heart disease. The occurrence of heart failure was unrelated to dose or time on drug; in more than half of the patients, sotalol treatment was continued. On average, there was no decrease in ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

The depression of upper airway motor activity that develops during the rapid eye movement (REM) stage of sleep is a major factor allowing upper airway obstructions to occur in patients with sleep apnea syndrome. Microinjections of carbachol, a cholinergic agonist, into the dorsal pontine tegmentum of chronically instrumented cats produce REM sleep. In acutely decerebrate cats, carbachol induces postural atonia, eye movements and a depression of the motor output to respiratory pump and upper airway muscles. In lumbar motoneurons, the depression of activity is due to a glycinergic inhibition that has the same characteristics during natural REM sleep in chronic cats and carbachol-induced atonia in decerebrate cats (Neurophysiology, 57 (1987) 1118-1129). The mechanisms that lead to the suppression of upper airway motoneuronal activity during REM sleep are unknown. In this study, we assessed whether the depression of hypoglossal (XII) nerve activity induced by pontine carbachol injections is caused by inhibitory amino acids acting within the XII nucleus. In decerebrate, paralyzed and artificially ventilated cats, we recorded the activities of both XII nerves (genioglossal branches), one phrenic and a cervical motor branch (to monitor postural activity). Postural atonia and respiratory depression were induced by pontine carbachol injections. The inhibitory amino acid receptor antagonists, strychnine (glycine receptors) or bicuculline (GABAA receptors), were injected (100-250 nl; 1.0-2.5 mM) into one XII nucleus (the other served as control) in an attempt to reduce or abolish the depression subsequently induced by pontine carbachol. Prior to the carbachol injections, both antagonists caused similar elevations of XII nerve activity on the treated side (30-40%). However, following carbachol, the XII nerve activity on the treated side was depressed to about 25% of the (pre-antagonist and pre-carbachol) control level, whereas the depression on the untreated side was slightly greater, to 10-15% of the control. Additional injections of antagonists during the carbachol-induced depression produced no further increase in nerve activity. This minor effect of the antagonists on the carbachol-induced depression of XII nerve activity was in contrast to the marked disinhibitory effects that both antagonists had on the XII nerve response to electrical stimulation of the lingual nerve. The latter was used as a control for the ability of strychnine and bicuculline to exert disinhibitory effects within the XII nucleus. Thus, there is little, if any, contribution of these inhibitory amino acids to the depression of XII motoneurons during the carbachol-induced, REM sleep-like postural and respiratory depression; mechanisms other than fast synaptic inhibition must be involved.

The microinjection of carbachol into the pons of acute decerebrate cats elicits a REM sleep-like atonia and a profound suppression of respiratory motoneuronal activity (J. Appl. Physiol., 69 (1990) 2280-2289). To assess whether this suppression is mediated by medullary neurons that provide respiratory drive to motoneurons of the respiratory pump muscles (diaphragm and intercostals), we studied the effect of pontine carbachol on the activity of neurons of the ventral respiratory group (VRG) in decerebrate, vagotomized, paralyzed and artificially ventilated cats. VRG neurons were recorded extracellularly along with the activity of phrenic and intercostal (external and internal) nerves. Both inspiratory (I) and expiratory (E) VRG neurons had incrementing, ramp-like bursts of activity during their firing periods and were not vagal motoneurons. Carbachol produced a depression of the peak firing rate in most (42/57) neurons studied. However, five cells showed no change and ten had an increase in activity in spite of consistent depression at the motoneuronal level. For the total population of cells (34 I and 23 E), the peak firing was reduced to 88.5% +/- 16.3 (S.D.) of control. The simultaneously recorded phrenic activity was reduced to 77.9% +/- 11.5, while inspiratory intercostal activity fell to 63.4% +/- 21.6 and expiratory to 23.2% +/- 21.2 of control. The carbachol-induced changes in peak firing of both I and E cells were quantitatively similar, and positively correlated to changes in peak phrenic activity. Analysis of this correlation suggested that phrenic and intercostal activities will be depressed to some degree by carbachol even when the average VRG cell activity remains unchanged. In addition, our data show that VRG cells may receive a combination of inhibitory and excitatory inputs during the carbachol-induced depression of respiratory motoneurons. Thus, although some disfacilitation from VRG cells may occur, there must be additional inhibitory or disfacilitatory pathways that mediate the decrease in activity of both phrenic and intercostal motoneurons that accompanies the REM sleep-like atonia.

Microinjections of carbachol into the pons induce a state that resembles rapid eye movement (REM) sleep in intact cats and, in decerebrate, artificially ventilated cats, produce postural atonia accompanied by a powerful depression of the respiratory motor output. In this study, pontine carbachol was used in decerebrate, spontaneously breathing cats to assess the effects of mechanical and chemical respiratory reflexes on the magnitude and pattern of the carbachol-induced depression of breathing, and to determine whether the depression is altered in those animals in which rapid eye movements are present. Phrenic nerve activity and tidal volume were only transiently depressed at the onset of the carbachol-induced postural atonia, whereas the decrease in respiratory rate and the depressions of hypoglossal and intercostal activities persisted until the response was reversed by a pontine microinjection of atropine 15-101 minutes after the onset of carbachol response. Ventilation was reduced to 70% of control during the steady-state conditions. The irregularity of breathing, characterized by the inter-quartile ranges of the distributions of the peak phrenic nerve activity and respiratory timing, did not increase following pontine carbachol. Neither vagotomy nor vigorous eye movements were associated with increased breathing irregularity. This contrasts with the irregular breathing (with minor average changes in ventilation) typical of natural REM sleep. We propose that the carbachol-injected decerebrate cat provides a useful model of the depressant effects that neural events associated with REM sleep may have on breathing.

In decerebrate, paralyzed, vagotomized and artificially ventilated cats, serotonin (5-HT) and its analogues, microinjected into the hypoglossal (XII) motor nucleus, altered the activity of the genioglossal branch of XII nerve. 5-HT, carboxamidotryptamine maleate (5-CT) and DOI (1-5 mM) increased the activity by over 200%. Methysergide reversed this increase. Methysergide, mianserin, or ketanserin (100-250 nl, 1 mM) reduced the spontaneous hypoglossal activity by 20-50%. Buspirone, 8-OH-DPAT and (-)-propranolol were without effect. Thus, 5-HT provides a substantial tonic excitatory drive to XII motoneurons. The 5-HT receptors involved are likely to be type 1C or 2, but uncertainty regarding the affinity profiles of the drugs used in in vivo conditions in the cat precludes a definite identification.

1. The activity of eighty-seven bronchopulmonary vagal afferent neurones with unmyelinated axons (C fibres) was recorded extracellularly in the nodose ganglia of decerebrate, paralysed and artificially ventilated cats. On the basis of their response latencies following the right atrial injection of capsaicin or phenyldiguanide, the cells were classified as having their receptor endings within the reach of pulmonary (latency less than 3.5 s) or bronchial (latency above 3.5 s) circulation. 2. Pulmonary and bronchial receptor cells differed only slightly in their response characteristics (firing rate, burst duration) and the conduction velocity of their peripheral axons. Bronchial C fibres represented about 70% of the population studied. 3. The medullary distributions of the central branches of six pulmonary and six bronchial C fibres were determined by means of the antidromic mapping technique. The two receptor subtypes did not differ in their central projection patterns. 4. Rostral to the obex, the central branches of the bronchopulmonary C fibres were localized within the medial portions of the nucleus tractus solitarii (NTS) and area postrema, and were most densely distributed along the borders of the parvicellular subnucleus of the NTS. Caudal to the obex, the most dense branching was found in the dorsal portion of the commissural subnucleus. Projections to the contralateral NTS were found, but these were of a much lower density. 5. The central distribution of bronchopulmonary C fibres is compared to the projection patterns of vagal and glossopharyngeal afferents of other modalities that are involved in respiratory and cardiovascular control. This is discussed in relation to the concept of a modality-specific organization of the NTS.

The injection of carbachol into the pontine tegmentum of decerebrate cats evokes a postural motor atonia that has many of the characteristics of the atonia of natural rapid-eye-movement (REM) sleep (Morales et al. J. Neurophysiol. 57: 1118-1129, 1987). We have used the carbachol-injected decerebrate cat to study the changes in respiratory neuronal activity that accompany the atonia. The activities of representative respiratory motor nerves--phrenic, intercostal, and hypoglossal--and that of a motor branch of C4 were recorded in decerebrate, vagotomized, paralyzed, and artificially ventilated cats. After the microinjection of carbachol, there was a profound suppression of activity in all the nerves and a decrease in respiratory rate. This was a consistent stereotyped response in which the magnitude of the suppression of respiratory-related activity was phrenic (to approximately 65% of control) less than inspiratory intercostal (approximately 50%) less than hypoglossal (approximately 10%) less than expiratory intercostal (approximately 5%). The decrease in respiratory rate (to approximately 70% of control) was caused by a prolongation of both inspiratory and expiratory durations. Complete reversal of the carbachol effect was elicited by the microinjection of atropine into the same site as the carbachol injection. This allowed us to produce a second episode of atonia by the injection of carbachol into the contralateral pons. Thus we have demonstrated the existence of neural pathways originating in the cholinoceptive cells of the pons that have the potential to powerfully and differentially depress various respiratory motoneuronal pools and to reduce the respiratory rate. These pathways are likely to be activated along with the atonia of REM sleep.

Muscle atonia is a feature of normal rapid-eye-movement sleep (REMS). The suppression of accessory respiratory muscle activity has been investigated and a role for sleep-disordered breathing hypothesized, but the suppression of diaphragmatic activity has rarely been considered. We hypothesized that the activity of the diaphragm was suppressed by an area of the dorsolateral pons during REMS. Lesions in this region have previously been shown to abolish the atonia of REMS. The diaphragmatic electromyogram (EMG) activity was analyzed in five naturally sleeping cats before and after pontine lesions leading to REMS without atonia. Although respiratory timing parameters were not altered by the lesion, the inspiratory rate of rise was significantly increased in all cats, and the brief pauses (40-100 ms) in the diaphragmatic EMG normally seen in REMS were virtually abolished. We conclude that the dorsolateral pons has a role in suppressing diaphragmatic activation during REMS. This suppression affects the average rate of rise of diaphragmatic activity and also leads to brief intermittent complete cessation of ongoing muscle activity. These decrements in diaphragm activity could jeopardize ventilation during REMS.

Tonic inhibition of some respiratory muscles occurs as part of the generalized muscle atonia of rapid-eye-movement sleep (REMS). A second type of inhibition of the diaphragm during REMS, fractionations, consists of brief pauses in the diaphragmatic electromyogram (DIA EMG) in association with phasic events. Because motor inhibition can occur as part of the startle response, and the brain is highly activated during REMS, we hypothesized that the neural basis of the fractionations might be activation of a startle network. To test this hypothesis, tone bursts (100 dB, 20-ms duration at 15-s intervals) were applied to cats at a fixed inspiratory level in the DIA moving average during REMS, non-rapid-eye-movement sleep (NREMS), and wakefulness. Parallel sham studies (no tone applied) were obtained for each state. The response of the DIA EMG was averaged over 100 ms by using the tone pulse as a trigger, and the following parameters of the DIA EMG were measured: latency to peak and/or nadir, increment or decrement in activity, and duration of peak and/or nadir. After a tone, all five animals studied displayed a profound suppression of DIA activity during REMS (latency to nadir 42.4 +/- 10.0 ms, duration of suppression 35.9 +/- 17.6 ms). Similarly, DIA activity was suppressed in all cats during NREMS (latency to nadir 40.9 +/- 13.3 ms, duration 23.9 +/- 13.4 ms). An excitatory response was observed in only two cats during NREMS and wakefulness. The similarity of startle-induced DIA EMG pauses to spontaneous fractionations of DIA activity during REMS suggests that the latter result from activation of a central startle system.

The effects of intravenous injections of isoproterenol (0.5-2 microgram) on the responses of carotid body chemoreceptor afferents and on integrated phrenic activity were investigated in twelve anesthetized and three decerebrate, unanesthetized cats. All animals were paralyzed and artificially ventilated. Isoproterenol stimulated carotid chemoreceptor activity and this stimulation was augmented by both hypoxia and hypercapnia. Following an injection of isoproterenol, the ratio of the minute phrenic activity relative to mean carotid chemoreceptor activity was increased. Thus, the stimulation of inspiratory phrenic output exceeded the stimulation of the chemoreceptor afferent input, and the peripheral chemoreflex activity does not account for the entire ventilatory response. To distinguish between a direct effect of isoproterenol and a possible secondary effect mediated via an increased venous return and an increased PaCO2, the latencies of the response of carotid chemoreceptors to both isoproterenol and hypercapnia were compared before and after carbonic anhydrase inhibition by acetazolamide. After acetazolamide, the latency of the response to hypercapnia increased from 3.5 sec to 8 sec whereas the latency of response to isoproterenol increased less, from 4.7 sec to 6.3 sec. Thus, isoproterenol stimulation was not mediated by CO2-H+. Propanolol, which blocked the systemic vascular effect, only partially blocked the chemoreceptor stimulation caused by isoproterenol, indicting that the effect of isoproterenol on chemoreceptor activity was not due to systemic cardiovascular changes.

Racemic indacrinone is a potent loop diuretic with transient uricosuric properties in certain nonhuman primates and in man. After chronic treatment, hyperuricemia develops presumably because of enhanced proximal tubular urate reabsorption secondary to extracellular fluid volume contraction. The natriuretic and uricosuric activities are associated with both enantiomers, but the (-)-enantiomer is significantly more potent as a natriuretic agent than the (+). Acutely, in Cebus monkeys, both enantiomers appear to have similar uricosuric activity. The difference in the natriuretic potency between the two enantiomers provides the possibility of altering the enantiomer ratio from its naturally occurring 1:1 ratio to another combination which would enhance the uricosuric action [more (+) relative to (-)] while preserving the potent natriuretic action of the (-). In healthy volunteers, a 1:4 ratio [(-):(+)] was isouricemic after 7 days of treatment and a 1:8 mixture lowered mean serum urate by 13%. Presumably, the desired ratio of (-):(+) will be in the range 1:4-1:9. Further enhancement of the diuretic profile of this compound may be obtained by adding sufficient amiloride to produce isokalemia.

Diflunisal is a new salicylic acid derivative identified after a search for a compound with improved potency, enhanced gastrointestinal tolerance relative to its antiinflammatory activity, and a longer duration of action than that of aspirin. Animal and clinical studies have confirmed these properties. As an inhibitor of cyclooxygenase tested in vitro in a sheep seminal vesicle preparation, diflunisal was less potent than indomethacin but 10 to 20 times more active than aspirin. In addition, it was shown biochemically to act as a moderate free radical scavenger. Diflunisal is well absorbed from the gastrointestinal tract, is subject to dose-dependent pharmacokinetics (like aspirin), and reaches steady-state levels in a predictable fashion in most persons. The drug is excreted by the kidneys, and its apparent half-life is lengthened in the presence of renal failure. A number of drug interactions have been described. Diflunisal produces reversible effects on platelet aggregation when given in high doses, whereas aspirin produces irreversible aggregation at low doses. Measurements of fecal blood loss and endoscopic examinations have confirmed the improved gastrointestinal tolerance of diflunisal compared to aspirin.

1. The activity of pump (p.) cells, second-order neurones in the pulmonary stretch receptor pathway, was recorded extracellularly in the nucleus of the tractus solitarius (n.t.s.) of the decerebrate cat. Their firing was proportional to changes in lung volume but unrelated to the centrally determined respiratory rhythm. A systematic search of the n.t.s. for the location of p. cells was made and an assessment of their efferent projection to the contralateral n.t.s. was determined electrophysiologically by the antidromic mapping technique. 2. P. cells were located around, and in close proximity to, the solitary tract. The two sites of greatest density were ventromedial and dorsolateral to the tract, with lower concentrations found laterally and ventrolaterally. 3. For twelve of the thirty p. cells tested, evidence of a projection to the contralateral n.t.s. was obtained; in seven of these cells, axonal arborizations within the projection area were identified. Almost all the cells that sent axons to the contralateral n.t.s. were located dorsolateral to the tract; there was no evidence that cells in the ventromedial region had contralateral projections. 4. No evidence that R beta neurones project to the contralateral commissural and ventrolateral subnuclei was found. 5. No p. cells projected to the contralateral ventrolateral n.t.s. The site of projection and branching was consistently localized just caudal to the obex and medial to the solitary tract, in the caudal medial, and commissural subnuclei of the n.t.s. This same region has been shown to receive a dense, direct projection from pulmonary rapidly adapting receptors.

Adaptation to the reflex effects of sustained changes in lung volume on inspiratory duration (TI), expiratory duration (TE), and the phrenic neurogram was examined. Test inflations in gallamine-paralyzed dogs anesthetized with pentobarbital sodium were made during a 6-min trial while the animal was not ventilated: 2 min at functional residual capacity (FRC), 2 min at elevated airway pressure, and 2 min back at FRC. The dogs were hyperoxygenated and arterial PCO2 was kept constant by an infusion of tris (hydroxymethyl) aminomethane. The maintained inflations produced minimal changes in TI. On return to FRC, TI was prolonged in proportion to the magnitude of the prior inflation. In contrast, inflation produced marked prolongation of TE, which then adapted back toward preinflation values. On return to FRC, TE shortened initially to values below control. This shortening increased with greater prior lung inflations. The times to reestablish steady-state values upon return to FRC differed for TI (14.8 +/- 4.6 s) and TE (33.8 +/- 12.7 s). The magnitude of the phrenic neurogram at a fixed time from onset of inspiration and its slope were unchanged with inflation. These results indicate that respiratory phase durations are influenced not only by pulmonary afferent input within each respiratory cycle but also by prior vagal afferent activity that engages central processes with long, although different, time constants. Afferent input to the slow central process controlling TI is not gated to only one phase of the respiratory cycle.

Dietary sodium restriction reduces vascular smooth muscle, particularly renovascular, responsiveness to infused angiotensin II (AII), while the responsiveness of the adrenal and the AII-renin short feedback loop to AII is enhanced. To determine whether circulating AII mediates these changes in responsiveness, we studied 11 sodium-restricted and 9 sodium-replete normal subjects before and after 75 h of converting enzyme inhibitor pretreatment with MK421. All subjects received infusions of paraaminohippurate (PAH) to assess renal plasma flow during graded AII infusion (0.3-10 ng/kg X min) before and after MK421 administration. Plasma aldosterone, cortisol, PRA, AII, sodium, potassium, and PAH clearance were measured at the onset and end of each AII dose. In sodium-restricted subjects, preinfusion AII and aldosterone levels were significantly reduced, (P less than 0.001) to the range found in sodium-replete subjects, after 75 h of MK421 administration, whereas blood pressure and PAH responses to infused AII were significantly enhanced (P less than 0.01). Blood pressure and PAH responses to infused AII in sodium-replete subjects were not significantly modified by MK421 treatment, confirming that the drug effect was specific. In contrast, the plasma aldosterone increment and PRA decrement after AII infusion were similar before and after MK421 on both diets. Thus, sodium-modulated changes in PAH and blood pressure responsiveness to infused AII depend on circulating AII levels. However, circulating AII does not mediate sodium modulation of adrenal or PRA short-feedback loop responsiveness to infused AII. Two different mechanisms determine sodium modulation of tissue responsiveness to AII; in one, circulating AII via a receptor mechanism is the mediator, and in the other, some other factor(s) also linked to sodium intake must be responsible.

Features of the distribution, metabolism, elimination, and pharmacokinetics of the cephalosporins and cefoxitin must be considered when concentrations of these drugs in biological fluids are interpreted. The extensive (approximately 86%) binding of cefazolin to plasma protein may account for the smaller volume of distribution and slower rate of renal clearance than are observed for cefoxitin, which is less extensively (73%) bound to protein. Results of microbiological assays of drug in urine may be influenced by the extent of metabolism of the drugs, which is 33% for cephalothin but less than 2% for cefoxitin. Elimination of cephalosporins and cefoxitin occurs by both glomerular filtration and tubular secretion and can be inhibited by the concurrent administration of probenecid. The pharmacokinetics of cefoxitin may be described by a linear, two-compartment, open model that has been used to predict levels of drug achieved in serum and urine after various dose regimens, including administration by intravenous bolus or infusion. The bioavailability of intramuscularly administered cefoxitin is equivalent to that of intravenously administered cefoxitin and is 90% complete within 3-4 hr after the dose is given.

"MK-421" a new oral converting enzyme inhibitor was administered to 16 hypertensive patients in doses ranging between 2.5-40 mg once daily for periods of 6-18 weeks. The blood pressure, plasma renin activity, plasma angiotensin II, aldosterone and angiotensin converting enzyme activity were assessed before and during treatment. Blood pressure normalized in 11 patients and decreased significantly in the remaining 5, without significant changes in heart rate or orthostatic hypotension. At 24 hrs after the first effective dose, plasma renin activity remained elevated to 228% whereas plasma angiotensin II was suppressed to 58%, aldosterone was suppressed to 40% and angiotensin converting enzyme activity was suppressed to 16% of the baseline. Magnitude of blood pressure decrement achieved with the maximal dose did not correlate with baseline plasma renin activity levels. No side-effects were noted during the 6-18 week period of observation.

A method for the measurement of the beta-blocker timolol and its 13C3-labeled analog in human plasma is described. A known amount of an internal standard, [2H9]timolol, is added to each plasma sample. The method employs a reversed-phase C18 cartridge for isolation of the drug-containing fraction, capillary column GLC of the trimethylsilyl derivatives, and detection via selected-ion monitoring. The ions monitored for quantification (m/e 86 from timolol and m/e 89 and 95 from the 13C3- and 2H9-labeled analogs, respectively) arise from the side chains of the three compounds [e.g., CH2N+HC(CH3)3 for m/e 86]. Plasma levels of timolol and [13C3]timolol in human subjects given 5 or 10 mg of each compound were followed simultaneously for 12 hr postdosing. A detection level of 0.5 ng/ml of plasma was found. No evidence was found for a metabolic kinetic isotope effect since the ratios of the two species of drug in the plasma samples were the same as the ratios in the administered dose.