Salt restriction for treatment of hypertension - current state and future directions.

PURPOSE OF REVIEW: Given the adverse effects of excess dietary sodium chloride (also known as table salt) on blood pressure (BP) and cardiovascular disease (CVD), restriction of dietary sodium is recommended by numerous guidelines. The strictest of these recommend no more than 1.5 g/day of dietary sodium among hypertensive persons. However, average dietary sodium intake in the population is closer to 5 g/day and there is debate about whether too much sodium restriction may be associated with increased CVD risk. Herein, we aim to provide a balanced update on this topic. RECENT FINDINGS: In 2021, the Salt Substitute and Stroke Study (SSaSS) demonstrated a significant reduction in BP, CVD, and death among Chinese adults randomized to a low sodium salt-substitute supplemented with potassium. This trial largely puts to rest any remaining debate about the benefits of dietary sodium restriction among persons with excess baseline intake (dietary sodium intake fell from approximately 5 down to 4 g/day in the active arm of SSaSS). However, whether achieving and maintaining a dietary sodium of less than1.5 g/day is feasible in real-world settings and whether this low an intake is harmful remain open questions. SUMMARY: Aiming for sodium intakes of 2--3 g/day in the general population and as low as 2 g/day in persons with hypertension or CVD seems most reasonable, but there is some uncertainty around lower targets.

Numbers of close contacts of individuals infected with SARS-CoV-2 and their association with government intervention strategies.

BACKGROUND: Contact tracing is conducted with the primary purpose of interrupting transmission from individuals who are likely to be infectious to others. Secondary analyses of data on the numbers of close contacts of confirmed cases could also: provide an early signal of increases in contact patterns that might precede larger than expected case numbers; evaluate the impact of government interventions on the number of contacts of confirmed cases; or provide data information on contact rates between age cohorts for the purpose of epidemiological modelling. We analysed data from 140,204 close contacts of 39,861 cases in Ireland from 1st May to 1st December 2020. RESULTS: Negative binomial regression models highlighted greater numbers of contacts within specific population demographics, after correcting for temporal associations. Separate segmented regression models of the number of cases over time and the average number of contacts per case indicated that a breakpoint indicating a rapid decrease in the number of contacts per case in October 2020 preceded a breakpoint indicating a reduction in the number of cases by 11 days. CONCLUSIONS: We found that the number of contacts per infected case was overdispersed, the mean varied considerable over time and was temporally associated with government interventions. Analysis of the reported number of contacts per individual in contact tracing data may be a useful early indicator of changes in behaviour in response to, or indeed despite, government restrictions. This study provides useful information for triangulating assumptions regarding the contact mixing rates between different age cohorts for epidemiological modelling.

Estimation of the serial interval and proportion of pre-symptomatic transmission events of COVID- 19 in Ireland using contact tracing data.

BACKGROUND: The serial interval is the period of time between the onset of symptoms in an infector and an infectee and is an important parameter which can impact on the estimation of the reproduction number. Whilst several parameters influencing infection transmission are expected to be consistent across populations, the serial interval can vary across and within populations over time. Therefore, local estimates are preferable for use in epidemiological models developed at a regional level. We used data collected as part of the national contact tracing process in Ireland to estimate the serial interval of SARS-CoV-2 infection in the Irish population, and to estimate the proportion of transmission events that occurred prior to the onset of symptoms. RESULTS: After data cleaning, the final dataset consisted of 471 infected close contacts from 471 primary cases. The median serial interval was 4 days, mean serial interval was 4.0 (95% confidence intervals 3.7, 4.3) days, whilst the 25th and 75th percentiles were 2 and 6 days respectively. We found that intervals were lower when the primary or secondary case were in the older age cohort (greater than 64 years). Simulating from an incubation period distribution from international literature, we estimated that 67% of transmission events had greater than 50% probability of occurring prior to the onset of symptoms in the infector. CONCLUSIONS: Whilst our analysis was based on a large sample size, data were collected for the primary purpose of interrupting transmission chains. Similar to other studies estimating the serial interval, our analysis is restricted to transmission pairs where the infector is known with some degree of certainty. Such pairs may represent more intense contacts with infected individuals than might occur in the overall population. It is therefore possible that our analysis is biased towards shorter serial intervals than the overall population.

Changes in the harmonic components of the flicker electroretinogram during light adaptation.

PURPOSE: To evaluate the nature and extent of changes in the fundamental and harmonic components of the 31-Hz flicker electroretinogram (ERG) during light adaptation. METHODS: Full-field ERGs were recorded from five visually normal subjects (ages 21-60 years). Following 30 min of dark adaptation, the subjects were exposed to a uniform adapting field of 50 cd/m(2). The field, which was presented for approximately 15 min, was intermittently modulated sinusoidally at 31.25 Hz. The ERG was recorded during the sinusoidal modulation, and Fourier analysis was used to obtain the amplitude and phase of the fundamental (F), second (2F), and third (3F) harmonic response components. RESULTS: F amplitude increased by almost a factor of two over approximately 6 min (time constant, τ, of 3.0 min). The 2F amplitude increased by a smaller amount, a factor of 1.4, and the time-course was approximately eight times faster than that of F (τ = 0.4 min). The 3F amplitude increased by a factor of 4.6, an increase that was larger than F or 2F, with a time-course that was between that of F and 2F (τ = 1.4 min). F phase was unaffected by light adaptation, whereas the 2F and 3F phases both increased by approximately 45° over similar time-courses (τ = 2.0 min). CONCLUSIONS: Light adaptation had different effects on the fundamental, second, and third harmonic components of the 31-Hz flicker ERG, which resulted in a change in waveform shape during light adaptation. The previously reported flicker ERG amplitude growth is driven primarily, but not entirely, by changes in the fundamental.

Pericardial Tuberculosis in a Non-endemic Region Presenting as a Persistent Upper Respiratory Tract Infection With Negative Serology, Bronchial Washings, and Pleural Aspirate.

This paper reports on the unlikely case of a 68-year-old man presenting with a non-resolving, mild lower respiratory tract infection, subsequently diagnosed with pericardial tuberculosis (TB) in the absence of TB risk factors and with negative TB serology. Pericardial and pleural effusions were found incidentally on CT pulmonary angiogram, with a small pericardial effusion without tamponade seen on the echocardiogram. During his three-month inpatient stay, the patient was rarely very unwell, though no treatment led to clinical and biochemical resolution of symptoms. Later deterioration prompted another echocardiogram, which found a moderate-sized pericardial effusion, septal bounce, and new regional wall motion abnormalities. To avert the impending cardiac tamponade, the patient underwent pericardiectomy, which provided a tissue diagnosis of TB. Pericardial TB is extremely uncommon, especially outside of TB endemic regions, though it is well described. This case is especially noteworthy, as serology, bronchial washings, and pleural aspirate had been negative for TB though a Quantiferon test was positive. The diagnosis was only confirmed after pericardiectomy. The patient was subsequently treated with anti-TB therapy, with a good clinical response. This case highlights diagnostic challenges and strategies for investigating and managing similar complex scenarios, particularly in non-endemic settings.

Predictors of Conduction Disturbances Requiring New Permanent Pacemaker Implantation following Transcatheter Aortic Valve Implantation Using the Evolut Series.

(1) Background: Conduction disturbance requiring a new permanent pacemaker (PPM) after transcatheter aortic valve implantation (TAVI) has traditionally been a common complication. New implantation techniques with self-expanding platforms have reportedly reduced the incidence of PPM. We sought to investigate the predictors of PPM at 30 days after TAVI using Evolut R/PRO/PRO+; (2) Methods: Consecutive patients who underwent TAVI with the Evolut platform between October 2019 and August 2022 at University Hospital Galway, Ireland, were included. Patients who had a prior PPM (n = 10), valve-in-valve procedures (n = 8) or received >1 valve during the index procedure (n = 3) were excluded. Baseline clinical, electrocardiographic (ECG), echocardiographic and multislice computed tomography (MSCT) parameters were analyzed. Pre-TAVI MSCT analysis included membranous septum (MS) length, a semi-quantitative calcification analysis of the aortic valve leaflets, left ventricular outflow tract, and mitral annulus. Furthermore, the implantation depth (ID) was measured from the final aortography. Multivariate binary logistic analysis and receiver operating characteristic (ROC) curve analysis were used to identify independent predictors and the optimal MS and ID cutoff values to predict new PPM requirements, respectively; (3) Results: A total of 129 TAVI patients were included (age = 81.3 ± 5.3 years; 36% female; median EuroSCORE II 3.2 [2.0, 5.4]). Fifteen patients (11.6%) required PPM after 30 days. The patients requiring new PPM at 30 days were more likely to have a lower European System for Cardiac Operative Risk Evaluation II, increased prevalence of right bundle branch block (RBBB) at baseline ECG, have a higher mitral annular calcification severity and have a shorter MS on preprocedural MSCT analysis, and have a ID, as shown on the final aortogram. From the multivariate analysis, pre-TAVI RBBB, MS length, and ID were shown to be predictors of new PPM. An MS length of <2.85 mm (AUC = 0.85, 95%CI: (0.77, 0.93)) and ID of >3.99 mm (area under the curve (AUC) = 0.79, (95% confidence interval (CI): (0.68, 0.90)) were found to be the optimal cut-offs for predicting new PPM requirements; (4) Conclusions: Membranous septum length and implantation depth were found to be independent predictors of new PPM post-TAVI with the Evolut platform. Patient-specific implantation depth could be used to mitigate the requirement for new PPM.

Treatment-resistant priapism associated with long-term low-molecular-weight heparin.

This case report summarises the case of a 56-year-old man with low-flow, ischaemic priapism requiring urgent insertion of a penile prosthesis following prophylactic anticoagulation with tinzaparin. Low-molecular-weight heparin (LMWH) has been proposed as a cause of ischaemic priapism, although reported cases of this are rare. This particular side effect of tinzaparin has been reported once in a case report in 2018, and there are scant other reports of LMWH-induced priapism. This case was refractory to the full treatment algorithm, including multiple aspirations, phenylephrine injection, cavernosal shunt and required transfer for implantation of a penile prosthesis. Only one other case of such a severe case of priapism has been documented, involving LMWH and warfarin. Documented evidence of possible causes of priapism are vital, given the rarity of this condition, the frequency of LMWH and the potentially devastating complications.

Episodic hypoxia induces long-term facilitation of upper airway muscle activity in spontaneously breathing anaesthetized rats.

We performed these experiments to determine if repeated exposure to episodic hypoxia induces long term facilitation (LTF) in anaesthetized spontaneously breathing rats. A previous study in spontaneously breathing rats was unable to demonstrate evidence of LTF with repeated hypoxia, but this may have been due to the low number of hypoxic episodes used. We hypothesized that with sufficient exposure, episodic hypoxia LTF of genioglossus (GG), hyoglossus (HG) and diaphragm (Dia) activities would be elicited. Experiments were performed in 24 anaesthetized spontaneously breathing rats with intact vagi. Peak and tonic GG, HG and Dia EMG activities were recorded before, during and for 1 h following exposure to eight (n = 8) or three (n = 8) episodes of isocapnic hypoxia ( = 0.1) each of 3 min duration. A third time control series was also performed with exposure to normoxia alone ( = 0.28, n = 8). Short-term potentiation of GG and HG muscle activity developed during the early period after repeated exposure to eight and three hypoxic episodes. LTF, however, occurred only after eight hypoxic episodes. This manifested as an increase in peak GG and Dia inspiratory muscle activity and tonic HG activity. LTF of respiratory breathing frequency was also induced, reflected by a reduction in inspiratory and expiratory time. These findings support our initial hypothesis that LTF in the anaesthetized, spontaneously breathing rat is dependent on the number of exposures to hypoxia and show that the responses to repetitive hypoxia are composed of both short and long-term facilitatory changes.

Long-term facilitation of upper airway muscle activity induced by episodic upper airway negative pressure and hypoxia in spontaneously breathing anaesthetized rats.

Obstruction of the upper airway (UA) is associated with episodes of hypoxia and upper airway negative pressure (UANP). In the companion paper it is shown that episodic hypoxia elicits long-term facilitation (LTF) of tongue protrudor, retractor and respiratory pump muscle activity. However, whether repeated exposure to UANP also induces LTF is unknown. We hypothesized that repetitive exposure to UANP would induce LTF of UA and respiratory pump muscle activity and when coupled with hypoxia, as occurs when the UA obstructs, would lead to an even greater facilitation of muscle activity and the response to UANP. Experiments were performed in 24 anaesthetized, spontaneously breathing rats with intact vagi. To induce LTF, UANP stimuli (-10 cmH(2)O) of 5 s duration were delivered every 30 s for 3 min (+/- hypoxia). This was repeated eight times over 1 h, each 3 min episode separated by 5 min of normoxia. Genioglossus (GG), hyoglossus (HG) and diaphragm (Dia) muscle activity was recorded before, during and for 1 h following the last exposure to episodic UANP alone (n = 8), UANP and hypoxia together (n = 8) or normoxia alone (n = 8). During the final hour, single pulses of UANP were applied at 1 min and every 10 min thereafter to determine whether LTF of the response to UANP had been induced. Our results show that LTF of GG muscle activity and its response to UANP was induced following exposure to episodic UANP stimuli alone and UANP applied during hypoxia. However, there was no significant difference between these responses. Episodic UANP alone also induced LTF of HG muscle activity but this effect did not manifest until 40 min following the last episode of repeated UANP stimulation. In the presence of hypoxia, no LTF of HG muscle response to UANP was found. In conclusion, episodic UANP stimulation induces LTF of UA dilator and retractor tongue muscles, but no further facilitation occurs when coupled with hypoxia. This response may serve as an important protective mechanism of respiratory homeostasis during sleep, particularly in patients who suffer from obstructive sleep apnoea.

Improved surface EMG electrode for measuring genioglossus muscle activity.

Activation of the genioglossus (GG) muscles is necessary to maintain the patency of the upper airway. In the condition of obstructive sleep apnea (OSA) this mechanism fails and the possible role of fatigue in its pathogenesis is still not fully understood. In this paper, a new electrode design for recording the genioglossus surface electromyogram (sEMG) is presented. The new design differs from a widely used GG surface electrode in both electrode configuration (unilateral rather than bilateral) and electrode material (Ag-AgCl rather than stainless steel (SS)). The separate effects of these factors were evaluated during force-varying and fatiguing contractions on normal human subjects and using GG sEMG model simulations. Unilateral sEMG was found to have lower amplitude, lower frequency content and a different rate of change of median frequency during fatiguing contractions. It was shown to overcome several disadvantages posed by the bilateral configuration and be more selective. Ag-AgCl has more favorable impedance characteristics and resulted in greater signal amplitudes. It was concluded that the new design is more suitable for detecting GG sEMG and allows more reliable interpretation of changes in sEMG due to physiological mechanisms, thus providing a new methodology for studying GG function and the role of fatigue in OSA.

Design of surface electrode array for measuring conduction velocity in the human genioglossus muscle.

A new appliance, incorporating linear arrays of pin electrodes for genioglossus (GG) surface electromyography measurement, is presented. This design enables the estimation of GG muscle fiber conduction velocity, which decreases with fatigue. The performance of the device was evaluated for ten healthy human subjects during fatiguing and force varying contractions.

Superior laryngeal and hypoglossal afferents tonically influence upper airway motor excitability in anesthetized rats.

Upper airway (UA) muscle activity is stimulated by changes in UA transmural pressure and by asphyxia. These responses are reduced by muscle relaxation. We hypothesized that this is due to a change in afferent feedback in the ansa hypoglossi and/or superior laryngeal nerve (SLN). We examined 1) the glossopharyngeal motor responses to UA transmural pressure and asphyxia and 2) how these responses were changed by muscle relaxation in animals where one or both of these afferent pathways had been sectioned bilaterally. Experiments were performed in 24 anesthetized, thoracotomized, artificially ventilated rats. Baseline glossopharyngeal activity and its response to UA transmural pressure and asphyxia were moderately reduced after bilateral section of the ansa hypoglossi (P < 0.05). Conversely, bilateral SLN section increased baseline glossopharyngeal activity, augmented the response to asphyxia, and abolished the response to UA transmural pressure. Muscle relaxation reduced resting glossopharyngeal activity and the response to asphyxia (P < 0.001). This occurred whether or not the ansa hypoglossi, the SLN, or both afferent pathways had been interrupted. We conclude that ansa hypoglossi afferents tonically excite and SLN afferents tonically inhibit UA motor activity. Muscle relaxation depressed UA motor activity after section of the ansa hypoglossi and SLN. This suggests that some or all of the response to muscle relaxation is mediated by alterations in the activity of afferent fibers other than those in the ansa hypoglossi or SLN.

Effects of topical anesthesia on upper airway resistance during wake-sleep transitions.

Deformation of the upper airway (UA) by negative transmural pressure alters the activity of UA mechanoreceptors, causing a reflex increase in UA muscle activity. Topical anesthesia of the UA mucosa, which greatly reduces this reflex response, causes an increase in UA resistance during stage 2 sleep. We hypothesized that topical anesthesia of the UA mucosa would predispose to UA instability at sleep onset and, therefore, examined the effect of UA anesthesia on pharyngeal resistance (Rph) in stage 1 sleep. Eleven normal, healthy volunteers were instrumented to record standard polysomnographic variables, respiratory airflow, and UA pressure at the nasal choanae and the epiglottis. Subjects were permitted to sleep until stable stage 2 sleep was reached and were then awoken. This procedure was repeated three times to obtain reproducible wake-sleep transitions. The UA mucosa was then anesthetized with 10% lidocaine to the oropharynx and laryngopharynx, and the pharyngeal mechanics were studied during the subsequent wake-sleep transition. Three subjects were excluded because of failure to resume sleep postanesthesia. Rph was significantly higher after anesthesia during stage 1 sleep [2.88 +/- 0.77 cmH(2)O.l(-1).s (mean +/- SE)] compared with control (0.95 +/- 0.35 cmH(2)O.l(-1).s; P < 0.05), but there was no difference during wakefulness. Furthermore, there was a significant rise in Rph at wake-to-sleep transitions and a significant fall in Rph at sleep-to-wake transitions after anesthesia (P < 0.05) but not in the control condition. We conclude that sensory receptors in the UA mucosa contribute to the maintenance of UA patency at wake-sleep transition in normal humans.

Simultaneous recording of breathing and respiratory related neuronal activity in the brainstem of conscious rats.

One aim of integrative neurophysiology is to understand the relationship between neuronal activity and normal evolution of other physiological parameters. In this respect, anaesthetics or paralyzing agents, that have been shown to have a significant effect on several vital physiological processes, can be seen as a real problem for the interpretation of observations. Eletrophysiological recording in awake animals avoids this problem. Recordings in forebrain areas are now used routinely but a number of specific difficulties have limited their application to the medullary areas. In this paper, we describe a preparation that allows us to simultaneously record neuronal activity in the dorsal brainstem and respiratory activity in awake rats, while applying different types of respiratory challenges.

Effect of upper airway negative pressure and lung inflation on laryngeal motor unit activity in rabbit.

Distortion of the upper airway by negative transmural pressure (UANP) causes reflex vagal bradycardia. This requires activation of cardiac vagal preganglionic neurons, which exhibit postinspiratory (PI) discharge. We hypothesized that UANP would also stimulate cranial respiratory motoneurons with PI activity. We recorded 32 respiratory modulated motor units from the recurrent laryngeal nerve of seven decerebrate paralyzed rabbits and recorded their responses to UANP and to withholding lung inflation using a phrenic-triggered ventilator. The phasic inspiratory (n = 17) and PI (n = 5) neurons detected were stimulated by -10 cmH(2)O UANP and by withdrawal of lung inflation (P < 0.05, Friedman's ANOVA). Expiratory-inspiratory units (n = 10) were tonically active but transiently inhibited in postinspiration; this inhibition was more pronounced and prolonged during UANP stimuli and during no-inflation tests (P < 0.05). We conclude that, in addition to increasing inspiratory activity in the recurrent laryngeal nerve, UANP also stimulates units with PI activity.

Upper airway muscle paralysis reduces reflex upper airway motor response to negative transmural pressure in rat.

The reflex upper airway (UA) motor response to UA negative pressure (UANP) is attenuated by neuromuscular blockade. We hypothesized that this is due to a reduction in the sensitivity of laryngeal mechanoreceptors to changes in UA pressure. We examined the effect of neuromuscular blockade on hypoglossal motor responses to UANP and to asphyxia in 15 anesthetized, thoracotomized, artificially ventilated rats. The activity of laryngeal mechanoreceptors is influenced by contractions of laryngeal and tongue muscles, so we studied the effect of selective denervation of these muscle groups on the UA motor response to UANP and to asphyxia, recording from the pharyngeal branch of the glossopharyngeal nerve (n = 11). We also examined the effect of tongue and laryngeal muscle denervation on superior laryngeal nerve (SLN) afferent activity at different airway transmural pressures (n = 6). Neuromuscular blockade and denervation of laryngeal and tongue muscles significantly reduced baseline UA motor nerve activity (P < 0.05), caused a small but significant attenuation of the motor response to asphyxia, and markedly attenuated the response to UANP. Motor denervation of tongue and laryngeal muscles significantly decreased SLN afferent activity and altered the response to UANP. We conclude that skeletal muscle relaxation reduces the reflex UA motor response to UANP, and this may be due to a reduction in the excitability of UA motor systems as well as a decrease of the response of SLN afferents to UANP.

Glycine at hypoglossal motor nucleus: genioglossus activity, CO(2) responses, and the additive effects of GABA.

There is evidence for glycine and GABA(A)-receptor-mediated inhibition of hypoglossal motoneurons in vitro. However, comparable studies have not been performed in vivo, and the interactions of such mechanisms with integrative reflex respiratory control have also not been determined. This study tests the hypotheses that glycine at the hypoglossal motor nucleus (HMN) will suppress genioglossus (GG) muscle activity, even in the presence of hypercapnic respiratory stimulation, and the effects of glycine will be blocked by strychnine. We also determined whether coapplication of glycine and muscimol (GABA(A)- receptor agonist) to the HMN is additive in suppressing GG activity. Twenty-four urethane-anesthetized, tracheotomized, and vagotomized rats were studied. Diaphragm and GG activities, the electroencephalogram, and blood pressure were recorded. Microdialysis probes were implanted into the HMN for delivery of artificial cerebrospinal fluid (control), glycine (0.0001-10 mM), or muscimol (0.1 microM). Increasing glycine at the HMN produced graded suppression of GG activity (P < 0.001), although the GG still responded to stimulation with 7% inspired CO(2) (P = 0.002). Strychnine (0.1 mM) reversed the glycine-mediated suppression of GG activity, whereas combined glycine and muscimol were additive in GG muscle suppression. It remains to be determined whether the recruitment of such glycine and GABA mechanisms explains the periods of major GG suppression in behaviors such as rapid eye movement sleep.

Effects of sleep-wake state on the genioglossus vs.diaphragm muscle response to CO(2) in rats.

The effects of sleep on the ventilatory responses to hypercapnia have been well described in animals and in humans. In contrast, there is little information for genioglossus (GG) responses to a range of CO(2) stimuli across all sleep-wake states. Given the notion that sleep, especially rapid eye movement (REM) sleep, may cause greater suppression of muscles with both respiratory and nonrespiratory functions, this study tests the hypothesis that GG activity will be differentially affected by sleep-wake states with major suppression in REM sleep despite excitation by CO(2). Seven rats were chronically implanted with electroencephalogram, neck, GG, and diaphragm electrodes, and responses to 0, 1, 3, 5, 7, and 9% CO(2) were recorded. Diaphragm activity and respiratory rate increased with CO(2) (P < 0.001) across sleep-wake states with significant increases at 3-5% CO(2) compared with 0% CO(2) controls (P < 0.05). Phasic GG activity also increased in hypercapnia but required higher CO(2) (7-9%) for significant activation (P < 0.05). Further studies in 15 urethane-anesthetized rats with the vagi intact (n = 6) and cut (n = 9) showed that intact vagi delayed GG recruitment with hypercapnia but did not affect diaphragm responses. In the naturally sleeping rats, we also showed that GG activity was significantly reduced in non-REM and REM sleep (P < 0.04) and was almost abolished in REM even with stimulation by 9% CO(2) (decrease = 80.4% vs. wakefulness). Such major suppression of GG activity in REM, even with significant respiratory stimulation, may explain why obstructive apneas are more common in REM sleep.

5-HT at hypoglossal motor nucleus and respiratory control of genioglossus muscle in anesthetized rats.

Serotonin (5-HT) from medullary raphe neurons excites hypoglossal motoneurons innervating genioglossus (GG) muscle. Since some raphe neurons also show increased activity in hypercapnia, we tested the hypothesis that serotonergic mechanisms at the hypoglossal motor nucleus (HMN) modulate GG activity and responses to CO2. Seventeen urethane-anesthetized, tracheotomized and vagotomized rats were studied. Microdialysis probes were used to deliver mianserin (5-HT receptor antagonist, 0 and 0.1 mM) or 5-HT (eight doses, 0-50 mM) to the HMN during room air or CO2-stimulated breathing. Mianserin decreased respiratory-related GG activity during room air and CO2-stimulated breathing (P<0.001), and also suppressed GG responses to CO2 (P=0.05). In contrast, GG activity was increased by 5-HT at the HMN, and was further increased in hypercapnia (P<0.02). However, 5-HT increased respiratory-related GG activity at levels lower (1 mM) than those eliciting tonic GG activity (10-30 mM 5-HT). The results show that 5-HT at the HMN contributes to the respiratory control of GG muscle.