Effect of blocking medial area of nucleus retrofacialis on respiratory rhythm

Experiments were performed on anaesthetized, vagotomized rabbits. Respiratory movement and phrenic rhythmical discharge were reversibly abolished by the symmetrical injection of 1% procaine into the medial area of the nucleus retrofacialis (mNRF). Blocking other areas of the medulla had no obvious effect on respiratory rhythm, with the exception of the rostral portion of the ventral respiratory group (VRG), which overlaps with the mNRF. When the mNRF was blocked, most inspiratory and expiratory neurons recorded in the VRG and DRG (dorsal respiratory group) gradually started to fire continuously, and no longer exhibited respiratory rhythm. A minority of respiratory neurons was inactivated during apnea. Stimulation of the caudal portion of the DRG and VRG evoked only a short cluster of phrenic discharges instead of rhythmical firing, indicating that the respiratory neurons situated in these areas cannot generate rhythmic activity by themselves. This suggests that the mNRF plays an important role in the genesis and maintenance of basic respiratory rhythm.     

Hypoglossal motoneuron responses to pulmonary and superior laryngeal afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the inspiratory discharges of the hypoglossal (whole nerve or single fibers), phrenic, and recurrent laryngeal nerves were compared, and the effects of pulmonary and superior laryngeal afferent inputs were observed. During lung inflations in phase with neural inspiration, hypoglossal and recurrent laryngeal activities differed from phrenic with respect to (a) burst onset times: both preceded the phrenic; (b) overall pattern: phrenic, augmenting; hypoglossal, decrementing; recurrent laryngeal, plateau-like. When inflation was withheld, the phrenic pattern was not markedly changed, but both hypoglossal and recurrent laryngeal became augmenting; the marked increase of hypoglossal activity (both whole nerve and single fiber) indicated strong inhibition by lung afferents. Superior laryngeal electrical stimulation evoked excitation of the contralateral phrenic (latency 4.1 msec) and the ipsilateral whole hypoglossal (latency 5.3 msec), followed by bilateral inhibitions (durations 20-30 msec); most hypoglossal fibers showed only inhibition. We conclude that, although both hypoglossal and phrenic outputs are driven by the inspiratory pattern generator(s), their promotor systems differ with respect to influences from central and peripheral inputs.     

Responses of recurrent laryngeal motoneurons to changes of pulmonary afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the discharges of the recurrent laryngeal (whole nerve or single fibers) and phrenic nerves, and the changes produced by pulmonary afferent inputs (lung inflation), were compared. When lung inflation was in phase with neural inspiration, four types of laryngeal fiber activities were observed: (a) phasic-inspiratory; (b) tonic-inspiratory; (c) expiratory-inspiratory; (d) early-expiratory. The firing patterns during inspiration were plateau-like, whereas the phrenic pattern was augmenting. When inflation was withheld, the plateau patterns usually became augmenting, indicating inhibition of laryngeal inspiratory activity by pulmonary afferents. Secondary effects of withholding inflation were (a) increases of early-expiratory activity (both whole nerve and individual fiber), indicating increased post-inhibitory rebound excitation; (b) decreased activity of tonic-inspiratory and expiratory-inspiratory fibers during early neural expiration, indicating increased inhibition by early-expiratory neurons. The discharge patterns of different types of laryngeal motoneuron, as well as their changes with inflation, are interpreted in relation to the function of regulating airway resistance.     

The role of vagal afferent information during inspiration in determining phrenic motoneurone output

Dogs were anaesthetised, paralysed and artifically ventilated using ramp inflations triggered by the onset of the 'integrated' phrenic signal. VT was initially adjusted to maintain a constant PaCO2 and the duration of inflation (TI(resp)) was adjusted to match the phrenic TI. With these control values of VT and TI(resp) a variety of experimental manoeuvres were performed to alter the pattern of volume information delivered during inspiration. These manoeuvres included: (1) alterations in VT while maintaining a constant TI(resp); (2) alterations in TI(resp) alone, with and without obstruction to expiration; (3) delays in the onset of inflation with and without a simultaneous reduction in TI(resp) and (4) the imposition of two inflations, each with the same reduced TI(resp) within the same inspiration. The results suggest that the pattern of vagally-mediated volume information during inspiration determines both the shape and the duration of phrenic motoneurone output. The importance of volume at inspiratory 'offswitch' as the sole determinant of TI is therefore denied. The rate of inflation was not found to contribute to the responses obtained.     

Respiration-related neurons in the medial nuclear complex of the solitary tract of the cat

Respiration-related (RR) neuronal activity was systematically searched for in the nuclear complex of the solitary tract (nTS) with special interest focused on regions located medially to the ventrolateral subnucleus (vlnTS) which is widely considered to be the anatomical location of the dorsal respiratory group (DRG). The experiments were carried out on cats under pentobarbitone anaesthesia, paralyzed and artificially ventilated. RR activity was recorded consistently not only in the vlnTS, but also in more medial regions. R alpha-type neurons were often encountered in ventral and medial aspects of the nTS. R beta-type neurons and expiration-related neurons were found also in ventral regions of the nTS. A small number of 'late onset' and 'early burst' inspiration-related neurons was found respectively in ventral and ventromedial regions of the nTS. The activity of neurons presenting a rhythmic pattern completely determined by lung volume changes due to the respirator was consistently recorded both in ventral and medial areas of the nTS. Most of these neurons were excited by lung inflation and displayed a discharge pattern characteristic of P-neurons. A few neurons, designated as 'inverse' P-neurons displayed an opposite behaviour, being inhibited by lung inflation. The results are consistent with both histological and neurophysiological studies showing that pulmonary stretch receptor afferents terminate also on the medial side of the solitary tract. It is suggested that the DRG is not restricted to the vlnTS, but comprises also neurons located in more medial regions of the nTS.     

Influence of lung volume on phrenic, hypoglossal and mylohyoid nerve activities

In decerebrate, paralyzed cats, ventilated by a servo-respirator in accordance with phrenic nerve activity, we examined the influence of lung volume on the activities of the phrenic, hypoglossal and mylohyoid nerves. When lung inflation was briefly withheld, the durations of inspiration (TI) and expiration (TE) and the activities of all three nerves increased. The relative increase in hypoglossal activity greatly exceeded that of phrenic activity and was apparent earlier in the course of inspiration. This hypoglossal response was enhanced by hypercapnia and isocapnic hypoxia. The responses of mylohyoid activity were quite variable: withholding lung inflation augmented inspiratory activity in some cats, but expiratory discharge in others. Sustained increases in end-expiratory lung volume were induced by application of 3-4 cm H2O of positive end-expiratory pressure (PEEP). Steady-state PEEP did not influence nerve activities or the breathing pattern. Bilateral vagotomy increased TI, TE, and the activities of all three nerves. No response to withoholding lung inflation could be discerned after vagal section. The results provide further definition of the influence of vagally mediated, lung volume dependent reflexes on the control of upper airway muscles. These reflexes are well suited to relieve or prevent upper airway obstruction.     

Activities of pulmonary stretch receptors during ventilatory cycles without lung inflation

When lung inflation is temporarily withheld in paralyzed, ventilated cats with intact vagi, the activities of inspiratory motor nerves are greater during the second cycle without inflation than during the first. This response is not easily attributable to increasing drive from chemoreceptors as it is abolished by vagotomy. We examined the hypothesis that the increasing inspiratory activity is the result of decreasing inhibitory feedback from pulmonary stretch receptors (PSRs). Decerebrate, paralyzed cats were ventilated by a servo-respirator in accordance with their own phrenic nerve activity. Afferent activities from individual PSRs were recorded from a few cut fibers of one vagus nerve; the vagi were otherwise intact. When lung inflation was withheld, phrenic and hypoglossal nerve activities and the durations of inspiration and expiration all increased and were significantly greater during the second cycle without inflation than during the first. The frequency of PSR discharge was also greater during the second cycle and thus did not account for the responses recorded from the motor nerves. We conclude that the latter responses probably reflect neural processes within the brain stem, involving a persistent inhibitory influence from lung inflation, which outlasts the inflation itself.     

Response of pancreatic polypeptide to a protein rich meal in diabetic autonomic neuropathy

The response of human pancreatic polypeptide (hPP) to a protein-rich meal was investigated in 4 groups of subjects: 1) normal controls (n = 11); 2) patients with recent onset type I diabetes, showing no sign of cardiovascular autonomic neuropathy (CAN) (n = 9); 3 and 4) patients with long standing type I diabetes without and with overt CAN (n = 12 and 10 respectively). Patients belonging the group 3 and 4 had equivalent duration of diabetes (17 and 20 years respectively). The mean integrated early hPP responses (0-30 minutes) were respectively (ng. min. ml-1; mean with range): 1) 9.4 (3.3-24.2); 2) 7.4 (0.7-22); 3) 4.8 (0-14.2); 4) 5.4 (0-14.9). The integrated total responses (0-120 minutes) were respectively: 1) 44.0 (12.7-98.7); 2) 39.0 (11.6-118.1); 3) 29.8 (0-81.2); 4) 25.9 (0-71.6). In the group with long standing diabetes, the early and total integrated hPP responses of the patients with CAN did not differ significantly from those without CAN. Early hPP responses of patients with long standing diabetes (group 3 and 4) were slightly (P less than 0.05) lower than those of controls. 5 patients with long standing diabetes had no detectable post-prandial hPP rise, a feature never observed in normals or recent onset diabetics. Two of these had no sign of CAN. These data suggest that an absence of hPP response to a mixed meal may be one of the expression of digestive autonomic neuropathy in long standing diabetes and that impaired hPP response may sometimes be dissociated from overt CAN.     

Phrenic afferent input to the lateral medullary reticular formation of the cat

The afferent inputs from phrenic nerve stimulation to the lateral reticular formation of the lower brain stem were studied in anesthetized spontaneously breathing cats. The activity of reticular neurons was recorded by means of extracellular tungsten microelectrodes. Electrical stimulation of the central end of the right phrenic nerve evoked excitatory or inhibitory responses in the lateral reticular nucleus (LRN), in the nucleus ambiguus (AMB) and in a region dorsal to the AMB of ipsi- and contralateral sides. Phrenic afferents belonging to the flexor reflex afferent group were involved in these responses. The discharge pattern of the respiratory related units (RRU) of the AMB were exceptionally affected by phrenic nerve stimulations. It is concluded that high threshold phrenic afferents relay in the LRN before projecting to the cerebellar cortex. The overlapping of respiratory and non-respiratory afferents in the reticular formation may participate to the adaptations of respiratory and somatomotor functions during specific behaviors.     

Cigarette smoking increases the risk of pancreatic calcification in late-onset but not early-onset idiopathic chronic pancreatitis

An association exists between cigarette smoking and pancreatitis owing to alcohol. We determined whether cigarette smoking affected the course of pancreatic calcification and insufficiency in idiopathic chronic pancreatitis. Medical records were analyzed of 24 persons with early- and 42 with late-onset idiopathic chronic pancreatitis who were diagnosed between 1976 and 1982 and then followed prospectively until 1985. Smoking equaled >5 pack-years before calcification or insufficiency or last follow-up. Mean follow-up after onset of chronic pancreatitis was 27 and 13 years in early- and late-onset idiopathic chronic pancreatitis, respectively. Incidence of calcification in the two groups was 58 and 43%, respectively. In early-onset idiopathic chronic pancreatitis, smokers and nonsmokers developed calcification at a similar rate and frequency (58%). In late-onset idiopathic chronic pancreatitis, smokers developed pancreatic calcifications faster (p < 0.001) and more frequently (83 vs. 13%, p < 0.001) than nonsmokers. The association between smoking and pancreatic calcification was independent of gender, body mass index, and exocrine or endocrine insufficiency. Smoking did not affect development of exocrine or endocrine insufficiency. Cigarette smoking increases the risk of pancreatic calcification of late- but not of early-onset idiopathic chronic pancreatitis. These data support encouraging cessation of smoking in chronic pancreatitis.     

Influence of phasic volume feedback on abdominal expiratory nerve activity

Our purpose was to examine the influence of phasic lung volume feedback on the activities of motor nerves innervating the diaphragm and transversus abdominis muscles during hypercapnia and hypoxia. We studied seventeen decerebrate cats that were paralyzed and ventilated with a servo-respirator controlled by the integrated phrenic neurogram. The effects of phasic lung volume feedback were assessed by withholding pulmonary inflation during the central inspiratory period. Withholding lung inflation for a single respiratory cycle under hyperoxic, normocapnic conditions consistently prolonged the durations of the inspiratory and expiratory periods, and caused marked increases in the peak electrical activities of both phrenic and abdominal nerves. Hyperoxic hypercapnia (PaCO2 50-80 mmHg) and isocapnic hypoxia (PaO2 60-35 mmHg) increased peak phrenic and abdominal neural activities, and withholding pulmonary inflation under these conditions caused even greater augmentations of inspiratory and expiratory motor output. The augmentation of expiratory activity by withholding lung inflation was proportionately greater than the concomitant prolongation of the central expiratory period. All responses to non-inflation maneuvers were abolished following bilateral cervical vagotomy. The results indicate that vagally mediated volume feedback during inspiration can attenuate the output of abdominal motoneurons in the subsequent expiratory period. Moreover, hypoxia, which attenuates abdominal motor activity in vagotomized animals, enhances this activity when the vagi are intact.     

Effects of hypercapnia on phrenic and stretch receptor responses to lung inflation

To determine if hypercapnia and reflex bronchoconstriction attenuate lung inflation effects on ventilatory activity by indirect effects on intrapulmonary stretch receptors (PSR), phrenic nerve activity and single unit PSR were monitored at controlled levels of static airway pressure (Paw) and arterial PCO2 in 15 anesthetized dogs. Paw in a vascularly isolated lung was varied between 2 and 14 cm H2O at levels of PaCO2 between 35 and 85 mm Hg. PSR activity (n = 38) in fine strands dissected from an otherwise intact vagus nerve and the integrated phrenic neurogram were recorded. The response to Paw varied from one PSR to another, but was consistent in a given unit; PaCO2 had no consistent effect on individual responses. Selected PSR (n = 15) were averaged to yield a population response to Paw; the selection criteria were: phrenic activity responded briskly to Paw and measurements were made at three levels of PaCO2. Average PSR discharge increased linearly with Paw but was unaffected by PaCO2. On the other hand, phrenic burst frequency decreased as Paw increased and hypercapnia attenuated the slope of this relationship. These results suggest that effects on the relationship between PSR activity and Paw cannot account for attenuation of the relationship between phrenic frequency and Paw in hypercapnia. The effect of PaCO2 on the phrenic frequency vs Paw relationship probably arises from integrative mechanisms in the central nervous system.     

Hyperpolarization-activated cyclic nucleotide-gated cation channel subtypes differentially modulate the excitability of murine small intestinal afferents

AIM:To assess the role of hyperpolarization-activated cyclic nucleotide-gated cation(HCN) channels in regulating the excitability of vagal and spinal gut afferents.METHODS:The mechanosensory response of mesenteric afferent activity was measured in an ex vivo murine jejunum preparation.HCN channel activity was recorded through voltage and current clamp in acutely dissociated dorsal root ganglia(DRG) and nodose ganglia(NG) neurons retrogradely labeled from the small intestine through injection of a fluorescent marker(DiI).The isoforms of HCN channels expressed in DRG and NG neurons were examined by immunohistochemistry.RESULTS:Ramp distension of the small intestine evoked biphasic increases in the afferent nerve activity,reflecting the activation of low-and high-threshold fibers.HCN blocker CsCl(5 mmol/L) preferentially inhibited the responses of low-threshold fibers to distension and showed no significant effects on the high-threshold responses.The effect of CsCl was mimicked by the more selective HCN blocker ZD7288(10 μmol/L).In 71.4% of DiI labeled DRG neurons(n = 20) and 90.9% of DiI labeled NG neurons(n = 10),an inward current(I h current) was evoked by hyperpolarization pulses which was fully eliminated by extracellular CsCl.In neurons expressing I h current,a typical "sag" was observed upon injection of hyperpolarizing current pulses in current-clamp recordings.CsCl abolished the sag entirely.In some DiI labeled DRG neurons,the I h current was potentiated by 8-Br-cAMP,which had no effect on the I h current of DiI labeled NG neurons.Immunohistochemistry revealed differential expression of HCN isoforms in vagal and spinal afferents,and HCN 2 and HCN 3 seemed to be the dominant isoform in DRG and NG,respectively.CONCLUSION:HCNs differentially regulate the excitability of vagal and spinal afferent of murine small intestine.     

The effect of antigen-induced bronchoconstriction on phrenic nerve activity

The effects of acute bronchoconstriction, produced by inhalation of Ascaris suum antigen, on both the amplitude and timing of phrenic nerve activity were studied in anesthetized dogs. Blood gas tensions and inspiratory air flow were maintained constant. Bronchoconstriction resulted in a significant increase in the magnitude and rate of rise of the phrenic neurogram during both normal respiratory cycles and cycles when lung inflation was prevented. The increase in the slope of the phrenic neurogram that results from lung inflation was further increased during bronchoconstriction. In addition, in half the animals, there was a significant increase in the tonic phrenic activity measured during expiration. All of these changes were abolished by bilateral cervical vagotomy. Antigen administration did not affect the timing of the different phases of the cycle equally; inspiratory duration was reduced by 51.8% and expiratory duration by 67.6%. Postinspiratory activity of the phrenic (PIIA) was reduced by only 34.7%; thus, during bronchoconstriction PIIA occupied a proportionally greater fraction of the expiratory phase. Vagotomy abolished the changes in respiratory timing and eliminated all PIIA.     

Functions of the retrofacial nucleus in chemosensitivity and ventilatory neurogenesis

The hypothesis was evaluated that neurons within the retrofacial nucleus of medulla integrate afferent stimuli from the central chemoreceptors. In decerebrate, vagotomized, paralyzed and ventilated cats, activity of the phrenic nerve was monitored. Peak integrated phrenic activity increased in hypercapnia; the frequency of phrenic bursts typically declined slightly. The retrofacial nucleus was ablated by radio-frequency lesions or neurons within this nucleus were destroyed by microinjections of kainic acid. Results were similar following lesions or injections. Following unilateral ablations, peak phrenic activity was greatly reduced at normocapnia and hypercapnia; the frequency of phrenic bursts typically rose. Both frequency and peak phrenic activity fell further after the contralateral destruction with a cessation of all phasic phrenic discharge being observed in most animals. Injections of kainic acid in regions rostral, caudal or medial to the retrofacial nucleus produced no consistent changes in phrenic activity. We conclude that neuronal activities in the region of the retrofacial nucleus are important both in the integration of stimuli from the central chemoreceptors and in defining the discharge patterns of respiratory neurons.     

The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: early- versus late-onset pre-eclampsia

The pathogenesis and aetiology of pre-eclampsia (PE) is still unclear. We investigated the role of angiogenic, antiangiogenic and vasoactive factors in black South African women with early- and late-onset PE. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), soluble vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were determined using the ELISA technique, and placental mRNA expression levels of sFlt-1, VEGF, PlGF and AT1 receptors were determined using real-time PCR. Serum sFlt-1 levels were significantly elevated and PlGF significantly reduced in early-onset PE compared to the normotensive group. Placental VEGF mRNA expression levels were significantly reduced in the late-onset preeclamptic group compared with the normotensives. The placental mRNA expression of AT1 receptor in the late-onset pre-eclamptic group was relatively raised compared to the normotensives, suggesting hypersensitivity to pressor agents. We believe that the excess of serum sFlt-1 and reduced VEGF and PlGF levels favour an anti-angiogenic state and endothelial dysfunction leading to PE, and that the aetiology and pathogenesis of early- and late-onset PE differ.     

硫化氢对大鼠肠缺血再灌注后回肠收缩活性的保护作用

背景：肠缺血再灌注（I/R）在临床中较为常见,并可引起严重的并发症,目前仍缺乏有效的治疗药物。目的：研究硫化氢（H2S）对大鼠肠I/R后离体回肠收缩活性的影响及其机制。方法：24只Sprague-Dawley大鼠随机分为正常组、假手术组、I/R组（I1 h/R4 h）、H2S组（再灌注前20 min腹腔内注射硫氢化钠10μmol/kg）。记录离体回肠自发收缩频率和曲线下面积（AUC）,观察离体回肠对KCl（30 mmol/L）、乙酰胆碱（Ach）（10-5mol/L）、电场刺激（EFS）（30 V,10 Hz,1.00 ms,10 s）的反应。以免疫荧光染色检测肠肌间神经丛中Hu、胆碱乙酰转移酶（ChAT）阳性神经元表达。结果：与假手术组相比,I/R组和H2S组大鼠离体回肠自发收缩频率、对KCl和Ach的反应无明显改变。I/R组自发收缩AUC和对EFS的反应明显下降（P〈0.05）,Hu、ChAT阳性神经元表达均明显降低（P〈0.05）;给予H2S干预后,上述指标均明显升高（P〈0.05）。结论：H2S对大鼠肠I/R后回肠收缩活性可产生保护作用,其机制可能是减轻了肠神经元尤其是兴奋性神经元的损伤。     

Cross-organ sensitization of lumbosacral spinal neurons receiving urinary bladder input in rats with inflamed colon

BACKGROUND & AIMS: Clinical studies show that patients with irritable bowel syndrome and colonic diseases frequently experience sensory and motor dysfunctions of the urinary bladder. The aim of this study was to investigate the spinal neuronal mechanisms responsible for potential cross talk between these visceral organs. METHODS: Colonic inflammation was induced by dextran sulfate sodium (5%) in drinking water for 7-12 days (n = 12); another group of rats without dextran sulfate sodium (n = 12) was used as control. Extracellular potentials of single L6 to S2 spinal neurons were recorded in pentobarbital-anesthetized and paralyzed rats with dextran sulfate sodium-induced colitis or normal colon. Urinary bladder distention (0.5-2.0 mL; 20 seconds) was produced with saline inflation, and colorectal distention was induced by inflation of an air balloon (80 mm Hg; 20 seconds). RESULTS: A total of 58 of 153 (38%) and 55 of 152 (36%) spinal neurons responded to urinary bladder distention in dextran sulfate sodium-treated and control animals, respectively. The mean background activity of neurons excited by urinary bladder distention in rats with dextran sulfate sodium-induced colitis was significantly higher than in the control group. The threshold volume for excitatory responses to urinary bladder distention in rats with inflamed colon (0.024 +/- 0.09 mL; n = 30) was significantly lower than for control rats (0.062 +/- 0.016 mL; n = 31; P < .05). The stimulus-response curves of excitatory responses to graded urinary bladder distention were significantly increased for both viscerovisceral (urinary bladder distention and colorectal distention) convergent neurons and urinary bladder distention-receptive neurons in rats with colitis compared with control animals. CONCLUSIONS: Acute colitis sensitized lumbosacral spinal neurons receiving input from the urinary bladder. Thus, spinal neuronal hyperexcitability may be involved in central cross-organ sensitization of visceral nociception between the colon and urinary bladder.     

Clinical profile of early-onset and late-onset idiopathic chronic pancreatitis in South India

Background and Aim

Idiopathic chronic pancreatitis (ICP) is the most common form of chronic pancreatitis reported in India. There is paucity of literature on the prevalence and profiles of early- and late-onset forms of ICP in India.

Material and Methods

We compared the profile of early- and late-onset ICP in a patient population attending a tertiary care hospital in South India.

Results

Pain was the characteristic feature as more than 90 % with both early-onset and late-onset ICP had pain as the most significant symptom. Onset of pain was at age 14.9?±?7.7 years in early-onset and at 38.1?±?9.9 in late-onset ICP (p?<?0.001). There was considerable delay between onset of pain in early onset as compared to late-onset ICP. Diabetes was seen in 41.4 % in early-onset as compared to 69.1 % in late-onset ICP (p?<?0.001). Pancreatic exocrine insufficiency was seen in 34.4 % in early-onset as compared to 53.2 % in late-onset ICP (p?<?0.001). Increased prevalence of exocrine insufficiency and diabetes was observed in late-onset as compared to early-onset ICP. Univariate analysis showed that alcohol use, smoking, age, and family history of diabetes were significantly associated with diabetes. Multivariate analysis showed strong associations for diabetes with smoking (odds ratio (OR)?=?4.2), calcification (OR?=?7.7), as well as family history and age >40 years.

Conclusions

There were differences between early-onset and late-onset ICP in southern Indian patients. Diabetes was strongly associated with smoking and pancreatic calcification.