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Role of the chemoreceptor trigger zone in histamine-induced emesis.

1. In unanaesthetized dogs, the emetic action of histamine was studied after its injection into the cerebral venricles through chronically implanted cannulae in order to elucidate the role of the chemoreceptor trigger zone (CT-zone), situated in the area postrema, for this emesis.2. On injection into the lateral cerebral ventricle, about 10 times larger doses of histamine (3 mg) were required regularly to produce emesis, and it occurred after a longer latency than on injection into the fourth ventricle. This is in accord with an action of histamine on the CT-zone.3. After bilateral ablation of the CT-zone, intraventricular injections of histamine no longer produced emesis even when injected in doses which were three to four times greater than those which regularly elicited vomiting in dogs with intact CT-zone. The emesis produced in dogs by intraventricular injections of histamine is thus fully accounted for by an action on the CT-zone.4. Injections of chlorpromazine intramuscularly or of the two antihistamines cyclizine and mepyramine, either intramuscularly or into the lateral ventricle, prevented the emesis caused by histamine injected into the lateral ventricle. This protective action of the antihistamines-which did not extend to the emesis produced by oral copper sulphate-suggests the presence of histaminergic receptors in the CT-zone.

Animals↗

Role of the chemoreceptor trigger zone in cyclopropane induced emesis in dogs.

Inhalation of cyclopropane in dogs, by the closed circuit method, for a fixed period, produced an emetic response during recovery from anaesthesia. Bilateral surgical ablation of the emetic chemoreceptor trigger zone of the area postrema rendered the dogs refractory to several times (3-6) the threshold emetic dose of cyclopropane.

Anesthetics↗

Nature of histamine receptors in the emetic chemoreceptor trigger zone.

1 The protective effects of the intracerebroventicular (i.c.v.) administration of the H1-receptor antagonist, mepyramine and the H2-receptor antagonists, burimamide and metiamide on centrally induced histamine-emesis were studied in unanaesthetized dogs. 2 The PD50 values of intraventricular mepyramine, burimamide and metiamide against the 100% emetic dose of histamine (3.0 mg i.c.v.) were found to be approximately 200 mug, 20 mug and 20 mug respectively. 3 Although burimamide (i.c.v. or i.v.) afforded protection against histamine-induced emesis, there was no protection against intravenous apomorphine-or oral copper sulphate-induced emesis. 4 The results suggest that both H1- and H2-histamine receptors in the emetic chemoreceptor trigger zone of the area postrema are concerned in histamine-induced emesis.

Animals↗

Functional heartburn patients demonstrate traits of functional bowel disorder but lack a uniform increase of chemoreceptor sensitivity to acid.

BACKGROUND: Functional heartburn (FH) patients have a profound impact on the response to anti-reflux therapy of the nonerosive reflux disease (NERD) group as compared to the response of the erosive esophagitis group. Thus far, there is paucity of information about their physiological and clinical characteristics that may separate them from the other NERD patients. AIM: To compare physiological and clinical characteristics of patients with FH to their counterparts within the NERD group (NERD-positive [NERD+]). METHODS: Subjects with typical heartburn symptoms, at least twice a week, were evaluated by an upper endoscopy. Only those with normal esophageal mucosa were recruited into the study and underwent pH testing to assess esophageal acid exposure. The patients were divided into those with normal pH test (FH) and those with abnormal pH test (NERD+). The groups were compared for demographics, gastroesophageal reflux disease symptom characteristics, psychological profile, and reported quality of life. Additionally, the two patient groups were compared for stimulus response functions to acid, autonomic function response, and rate of Helicobacter pylori infection. RESULTS: Fifty-two patients included 30 with FH and the rest with NERD+. There was no statistical difference in demographics, frequency of hiatal hernia and H. pylori infection between the two groups. Patients with FH had a significantly longer history of heartburn and reported more episodes of chest pain than NERD+ patients (M--7.5 yr and M--once a week vs M--3.5 yr and M--once a month, respectively, p < 0.05). Patients with FH scored significantly higher in the somatization domain than patients with NERD+ (M--60 vs 52.5, p < 0.05), but had similar reported quality of life. Patients with NERD+ demonstrated a significantly shorter time to symptom perception and higher intensity rating (p < 0.05). Only patients with FH demonstrated a statistically significant increase in heart rate and skin conductance after acid perfusion, as compared to those with NERD+ (p < 0.05). CONCLUSION: Patients with FH demonstrate increased reports of chest pain and somatization, an alteration in autonomic function but lack a uniform increase in chemoreceptor sensitivity to acid as compared to those with NERD+. This suggests that while FH patients harbor clinical traits of a functional bowel disorder, hypersensitivity to acid is not a general phenomenon.

Autonomic Nervous System↗

Isolation of the arterial supply to the carotid and central chemoreceptors in the sheep.

The aim of our study was to develop and validate a simple surgical model in the sheep which allows control of the gas composition of the blood supplying the carotid and central chemosensitive area independently of the rest of the body. This approach was made possible due to the specific features of the cranial circulation in the sheep. An extracorporeal circuit, consisting of a pump and a gas exchanger, was placed at the level of the two common carotid arteries to create a pressure gradient between the carotid and the systemic systems and to reverse blood flow in the vertebral vessels via the occipital arteries. When a pressure gradient of about 40 Torr was created between the systemic and carotid circulation, we found that no blood could reach the carotid bodies and the medulla without passing though the extracorporeal circulation. This was established (1) by measuring vertebral blood flow; and (2) by injecting either a coloured suspension or particles labelled with (99m*)Tc into the systemic or the carotid circulation. The slope of the relationship between minute ventilation (V(E)) and systemic arterial P(CO2) (P(a,CO2)) during high CO(2) inhalation in seven hyperoxic vagotomised and anaesthetised sheep was dramatically reduced, but remained above zero, when P(a,CO2) was maintained constant in the cephalic circuit (0.11 +/- 0.15 vs. 0.70 +/- 0.35 l min(-1) Torr(-1) for the control tests). This residual V(E) response to CO(2) inhalation remains to be explained since it could not be accounted for by any of the chemical or circulatory changes occurring in the cephalic circulation. Nevertheless, this preparation provides an easy method of maintaining chemical and circulatory homeostasis at the chemoreceptor level.

Animals↗

The responses in renal nerves to stimulation of atrial receptors, carotid sinus baroreceptors and carotid chemoreceptors.

The reflex reduction in activity in renal sympathetic nerves in response to distension of small balloons in the pulmonary vein-atrial junctions was studied in dogs anaesthetized with chloralose; the carotid sinuses were isolated and perfused with blood. In the first group of dogs, the response to distension of the balloons was studied at different levels of carotid sinus pressure. In thirteen preparations of renal nerves in eight dogs the response was not significantly influenced when the mean carotid sinus pressure was changed from 9.5 kPa to 17.5 kPa, despite marked changes in control frequencies of activity in the nerves. In the second group of dogs, the response to distension of the balloons was studied when the carotid sinuses were perfused alternately with arterial and venous blood. In six preparations of renal nerves in five dogs the response was not significantly influenced when the blood perfusing the carotid sinuses was changed, despite marked changes in control frequencies of activity in the nerves. In a third group of dogs, the reflex reduction in activity in renal nerves in response to a step increase in pressure in one carotid sinus was examined at different levels of pressure in the contralateral carotid sinus. In six preparations of renal nerves in five dogs the response to an increase in pressure in one carotid sinus was significantly reduced when the mean pressure in the contralateral sinus was changed from 8.7 kPa to 17.1 kPa. It is concluded that there is no interaction between the projections of atrial receptors and carotid sinus baroreceptors or carotid chemoreceptors in their convergence on the same efferent renal neurones.

Animals↗

Respiratory inhibition from chicken intrapulmonary chemoreceptors reduced by increasing rate of repetitive PCO2 changes.

There is no functional residual capacity in the avian lung, so during inspiration the PCO2 of the gas entering the exchange region abruptly changes from its maximum, the dead space PCO2, to its minimum, the inspired PCO2. Dynamic responses of intrapulmonary chemoreceptors (i.p.c.s) to positive and negative going steps in PCO2 are asymmetrical and have maxima occurring at times comparable to inspiratory duration. Thus, the respiratory inhibition that i.p.c.s produce could depend on respiratory frequency. We tested this hypothesis by changing intrapulmonary PCO2 repetitively between 7 and 42 torr in the non-perfused left lungs of eight unidirectionally ventilated thoracotomized chickens. Right intrapulmonary and arterial PCO2 were kept constant. Respiratory movements were calibrated in terms of steady state intrapulmonary PCO2 levels. At PCO2 repetition rates comparable to normal respiratory frequency, respiratory movements were equal to those expected for an intrapulmonary PCO2 2--3 torr lower than the average of the two PCO2 levels used. This difference increased linearly as the logarithm of the repetition rate decreased. We conclude that respiratory inhibition by i.p.c.s is inversely related to respiratory rate as well as to average intrapulmonary PCO2 levels. Because respiratory frequency itself is negatively related to i.p.c. discharge frequency, i.p.c.s may provide control over respiratory frequency even if average PCO2 levels do not change.

Animals↗

The response in efferent cardiac sympathetic nerves to stimulation of atrial receptors, carotid sinus baroreceptors and carotid chemoreceptors.

The reflex increase in activity in efferent cardiac sympathetic nerve fibres in response to distension of small balloons in the pulmonary vein-atrial junctions was studied in dogs anaesthetized with chloralose; the carotid sinuses were isolated and perfused with blood. In the efferent cardiac nerves which responded to distension of the balloons there was no significant change in the control activity, or in the magnitude of the response during changes in carotid sinus pressure from 8 to 30 kPa, during changes in the blood perfusing the sinuses from arterial to venous or during stimulation of the cutaneous branch of the left radial nerve. In contrast, in efferent cardiac nerves which did not respond to the distension of the balloons, consistent and significant changes in activity resulted from stimulating arterial baroreceptors, chemoreceptors or a cutaneous branch of the radial nerve. It is concluded that efferent cardiac sympathetic nerve fibres which respond by an increase in activity to stimulation of the atrial receptors, constitute a group of nerve fibres which are separate from those responding to stimulation of receptors in the carotid region or to stimulation of peripheral somatic nerves.

Animals↗

Chicken intrapulmonary chemoreceptor discharge frequency reduced by increasing rate of repetitive PCO2 changes.

We have recently reported that repetitive changes of PCO2 given to innervated non-perfused chicken lungs reflexly inhibit respiratory efforts. The degree of respiratory inhibition is rate-dependent, decreasing as repetition rate is increased to 3 . 2 Hz (Barker, Burger & Nye, 1981) to nearly that expected from the average PCO2 of the two levels given. Intrapulmonary chemoreceptors (i.p.c.s), whose discharge frequencies are inversely related to PCO2, are presumably responsible for these effects. Here we report the activity of twenty single i.p.c.s in the left, non-perfused lungs of twelve thoractomized cockerels as PCO2 of the gas ventilating those lungs was repetively changed between 7 and 27 or 7 and 40 torr. Maximal discharge rates of individual receptors after a PCO2 decrease were related to the location of receptors within the gas exchange region. From 0 . 2 to 1 . 6 Hz both average and maximal discharge frequencies decreased. The inhibition of discharge in this range was greater than that predicted by the steady-state relationship between reflex responses and receptor discharge, suggesting that the reflex effects of i.p.c. discharge are not a simple function of the mean discharge frequency of all i.p.c.s. Either average i.p.c. discharge frequency per PCO2 cycle over-estimates their respiratory reflex inhibition or only the less rate-sensitive i.p.c.s, those in the middle of the gas exchange region, may dominate this rate-dependent respiratory reflex.

Animals↗

Changes in intrapulmonary chemoreceptor discharge in response to the adjustment of respiratory pattern during hyperventilation in domestic fowl.

It has been suggested that avian vagal intrapulmonary CO2-sensitive receptors (i.p.c.) may be capable of monitoring the rate and extent of CO2 wash-out from the lung during spontaneous breathing. The purpose of this study was to record i.p.c. discharge activity in spontaneously breathing domestic fowl when minute volume (VI) was elevated from resting levels. This was accomplished by administration of almitrine (2 mg X kg-1 I.V.), a respiratory stimulant drug that has been shown to have a specific long-lasting stimulatory action on carotid body chemoreceptors. Unanaesthetized decerebrate fowl were tracheotomized and single-unit activity was recorded from sixteen vagal i.p.c. When ventilation was elevated 2.2-fold by almitrine (initially by increases in tidal volume (VT)) i.p.c. discharge was increased in both inspiration and expiration, and the delay period before the onset of i.p.c. discharge in inspiration was markedly shortened. Within 5-10 min after the administration of almitrine, the breathing pattern changed to one of rapid, shallow breathing, although the 2.2-fold elevation of the rate of gas flow through the parabronchi (V) and mean inspiratory flow rate (VT/TI) were maintained. The i.p.c. continued to fire phasically, with peaks of discharge in both inspiration and expiration, though there were fewer spikes per breath and mean inspiratory peak discharge rate returned to control (eupnoeic) levels. It is concluded that i.p.c. discharge is increased when VI is elevated in the spontaneously breathing fowl and that the pattern of discharge is dependent on the pattern of breathing. I.p.c. show high dynamic sensitivity to changes in the PCO2 of their microenvironment and it is possible to explain the changes in discharge pattern observed in terms of the PCO2 changes in the lungs and air sacs. These results support proposals that the pattern of breathing is to some extent dependent upon the intensity and timing of i.p.c. activity.

Almitrine↗

Hypothalamic-evoked effects in cat nucleus tractus solitarius facilitating chemoreceptor reflexes.

In anaesthetized cats intracellular recordings in the nucleus tractus solitarius (NTS) have been used to identify neurones receiving inputs from the carotid sinus nerve (SN), the aortic nerve and hypothalamic defence area (HDA). In forty-four neurones activated by SN stimulation HDA activation evoked an IPSP in fourteen (32%) and an EPSP in eight (11%). Those neurones receiving an HDA-evoked IPSP, and tested for reflex inputs, responded only to baroreceptor activation. Neurones receiving HDA-evoked EPSPs responded only to chemoreceptor activation. In three neurones unaffected by SN stimulation, short latency inputs from HDA were observed, suggesting direct monosynaptic inputs.

Action Potentials↗

Cyanide stimulation of the systemic arterial chemoreceptors in foetal lambs.

1. In foetal lambs, delivered by Caesarean section under light chloralose anaesthesia, injection of sodium cyanide into the left atrium or ascending aorta caused a rise of arterial pressure and femoral vasoconstriction. The response to 0.77 mg/kg was barely present at 0.6 of term; by 0.8 of term there was a large response to one third of this dose.2. The cardiovascular response to cyanide injection into the left atrium or ascending aorta was diminished either by section of the vagi or by carotid denervation, and was abolished by cutting both sets of nerves.3. Injection of sodium cyanide into both common carotids simultaneously caused a substantial cardiovascular response and often a respiratory effort, abolished by carotid denervation, whereas injection into a single carotid rarely caused an effect.4. It is concluded that the carotid chemoreceptors in mature foetal lambs can be excited by a stimulus of sufficient intensity, even though they do not respond to moderate hypoxaemia.

Animals↗

The location of the chemoreceptor controlling gastric acid secretion during hypoglycaemia.

1. The injection of 2-deoxy-D-glucose directly into the lateral hypothalamic area of rats, but not elsewhere, caused a prompt and sustained secretion of acid by the stomach at a rate comparable to that due to insulin hypoglycaemia.2. Acid secretion provoked by such injections, like that resulting from hypoglycaemia, could be stopped by raising the plasma glucose concentration by the intravenous infusion of glucose.3. Unilateral intrahypothalamic injection of 2-deoxy-D-glucose activated both vagi for, although cutting one vagus reduced the secretion, division of both was necessary to abolish it.4. Gastric acid secretion evoked by a systemic stimulus (insulin-induced hypoglycaemia or intravenous 3-O-methylglucose) could be prevented by inactivating the lateral hypothalamic area on each side with phenol or lignocaine.5. It is concluded that there exists in the lateral hypothalamic area a chemoreceptor, responsive to a lack of metabolizable glucose, which can initiate and sustain the vagally mediated secretion of acid by the stomach.

Animals↗

The role of the carotid body chemoreceptors and carotid sinus baroreceptors in the control of cerebral blood vessels.

1. Cerebral blood flow was measured in 17 baboons, anaesthetized with pentobarbitone, paralysed with gallamine and mechanically ventilated and in which the right sinus and both aortic nerves had been cut and the left carotid sinus vascularly isolated. Later in each experiment, the head was artificially perfused with femoral arterial blood via the innominate artery.2. Stimulation of the carotid body chemoreceptors with venous blood invariably caused a rise in regional cerebral blood flow whether the head was naturally or artificially perfused. This response was almost completely abolished if the VIIth cranial nerves were cut intracranially.3. Regional cerebral blood flow varied inversely with carotid sinus pressure.4. After the remaining (left) sinus nerve had been cut, the cerebral vascular response to hypoxia was negligible and the response to hypercapnia was markedly reduced. Blood flow then varied with perfusion pressure.5. These results provide further evidence that cerebral blood vessels are reflexly controlled and that the peripheral arterial receptors are involved. Their action is most conspicuous in the vascular response to hypoxia and together with intrinsic factors in the cerebral vascular bed, they determine the size of the vascular response to changes in CO(2) and pressure.

Animals↗

Sensitivity of central chemoreceptors controlling blood glucose and body temperature during glucose deprivation.

1. The rise in blood glucose and the fall in body temperature which follows the injection of a glucose analogue, 2-deoxy-D-glucose (2-DG) into the lateral cerebral ventricle (I.C.V) of unanaesthetized rats were studied and found to be dose-dependent. These 2-DG induced responses are elicited by the impairment of glucose metabolism within central "glucoreceptors'. 2. 2DG induced hyperglycaemia and hypothermia were completely prevented and even the converse effects occurred when fivefold equimolar amounts of D-fructose were simultaneously injected I.C.V.; fructose, at equimolar doses, did not modify the effects of 2-DG. 3. D-xylose and D-ribose, even at high doses, did not influence 2-DG hyperglycaemia, but increased slightly the 2-DG induced hypothermia. This suggests that the pentose phosphate pathway is unable to support the metabolism within the glucoreceptors. 4. Pyruvate suppressed the 2-DG induced hyperglycaemia with a marked delay, while acetate (as ethyl ester) and a mixture of malate plus oxaloacetate did not prevent 2-DG induced effects. These results may be accounted for by the low dosage used. 5. Acetoacetate and 3-hydroxybutyrate did not prevent 2-DG hypothermia and hyperglycaemia. 6. An effective prevention of the 2-DG induced hyperglycaemia and hypothermia was achieved with fumarate and glutamate, indicating that the stimulation of the Krebs cycle within "glucoreceptors' removes the glucoprivic effects. 7. The results indicate that prevention of 2-DG induced effects occurred only with alternate source of metabolic fuel which can support high respiratory rates in brain tissue. It is concluded that central chemoreceptors are not specifically responsive to glucose, or hexoses, but to the rate of oxidative metabolism.

Acetates↗

Substance P-saporin lesion of neurons with NK1 receptors in one chemoreceptor site in rats decreases ventilation and chemosensitivity.

All medullary central chemoreceptor sites contain neurokinin-1 receptor immunoreactivity (NK1R-ir). We ask if NK1R-ir neurons and processes are involved in chemoreception. At one site, the retrotrapezoid nucleus/parapyramidal region (RTN/Ppy), we injected a substance P-saporin conjugate (SP-SAP; 0.1 pmol in 100 nl) to kill NK1R-ir neurons specifically, or SAP alone as a control. We made measurements for 15 days after the injections in two groups of rats. In group 1, with unilateral injections made in the awake state via a pre-implanted guide cannula, we compared responses within rats using initial baseline data. In group 2, with bilateral injections made under anaesthesia at surgery, we compared responses between SP-SAP- and SAP-treated rats. SP-SAP treatment reduced the volume of the RTN/Ppy region that contained NK1R-ir neuronal somata and processes by 44 % (group 1) and by 47 and 40 % on each side, respectively (group 2). Ventilation (.V(E)) and tidal volume (V(T)) were decreased during air breathing in sleep and wakefulness (group 2; P < 0.001; two-way ANOVA) and P(a,CO2) was increased (group 2; P < 0.05; Student's t test). When rats breathed an air mixture containing 7 % CO(2) during sleep and wakefulness, .V(E) and V(T) were lower (groups 1 and 2; P < 0.001; ANOVA) and the Delta.V(E) in air containing 7 % CO(2) compared to air was decreased by 28-30 % (group 1) and 17-22 % (group 2). SP-SAP-treated rats also slept less during air breathing. We conclude that neurons with NK1R-ir somata or processes in the RTN/Ppy region are either chemosensitive or they modulate chemosensitivity. They also provide a tonic drive to breathe and may affect arousal.

Animals↗

Presynaptic modulation of rat arterial chemoreceptor function by 5-HT: role of K+ channel inhibition via protein kinase C.

The peripheral control of breathing is mediated by O2-sensitive carotid body (CB) type 1 cells, which express multiple neurotransmitters including the monoamines, dopamine and serotonin (5-HT). Whereas dopamine has been extensively studied, 5-HT has received little attention. Here, to elucidate the role of 5-HT in CB chemotransmission, we used perforated-patch recording from rat type 1 cell clusters and co-cultured petrosal (afferent) neurones. 5-HT induced action potentials and/or membrane depolarization associated with a conductance decrease in approximately 40% of recordings from type 1 cells (n = 78/192). These responses were markedly inhibited by the 5-HT2 receptor antagonist ketanserin (10-50 microM) and by the protein kinase C (PKC) inhibitor chelerythrine (50 microM). The PKC activator 1-oleoyl-2-acetylglycerol (OAG; 50 microM) mimicked the 5-HT-induced depolarization, and the combined effects of 5-HT and OAG were non-additive. The 5-HT-induced responses reversed near the potassium (K+) equilibrium potential (at approximately -82 mV; EK = -83 mV), suggesting inhibition of a resting K+ conductance. In type 1 cells (n = 7), voltage-activated outward K+ current was also inhibited by 1-50 microM 5-HT, an effect that was prevented by PKC inhibitors (chelerythrine and NPC 15437) and mimicked by OAG; the outward K+ current inhibited by 5-HT appeared to be predominantly a Ca(2+)-dependent K+ current. The 5-HT2 receptor blockers ketanserin and ritanserin reversibly inhibited spontaneous action potentials and the hypoxia-induced receptor potential recorded from clustered type 1 cells. Moreover, these blockers reversibly inhibited the hypoxic chemosensory response recorded postsynaptically in petrosal neurones that functionally innervated type 1 clusters in co-culture. RT-PCR and confocal immunofluorescence techniques revealed 5-HT2a receptor expression in rat CB type 1 cells. These results suggest that release of endogenous 5-HT regulates CB chemoreceptor function presynaptically, by a positive feedback mechanism involving autocrine-paracrine stimulation of 5-HT2a receptors and PKC modulation of resting and Ca(2+)-dependent K+ conductances.

Animals↗

Nerve injury reduces responses of hypoglossal motoneurones to baseline and chemoreceptor-modulated inspiratory drive in the adult rat.

The effects of peripheral nerve lesions on the membrane and synaptic properties of motoneurones have been extensively studied. However, minimal information exists about how these alterations finally influence discharge activity and motor output under physiological afferent drive. The aim of this work was to evaluate the effect of hypoglossal (XIIth) nerve crushing on hypoglossal motoneurone (HMN) discharge in response to the basal inspiratory afferent drive and its chemosensory modulation by CO(2). The evolution of the lesion was assessed by recording the compound muscle action potential evoked by XIIth nerve stimulation, which was lost on crushing and then recovered gradually to control values from the second to fourth weeks post-lesion. Basal inspiratory activities recorded 7 days post-injury in the nerve proximal to the lesion site, and in the nucleus, were reduced by 51.6% and 35.8%, respectively. Single unit antidromic latencies were lengthened by lesion, and unusually high stimulation intensities were frequently required to elicit antidromic spikes. Likewise, inspiratory modulation of unitary discharge under conditions in which chemoreceptor drive was varied by altering end-tidal CO(2) was reduced by more than 60%. Although the general recruitment scheme was preserved after XIIth nerve lesion, we noticed an increased proportion of low-threshold units and a reduced recruitment gain across the physiological range. Immunohistochemical staining of synaptophysin in the hypoglossal nuclei revealed significant reductions of this synaptic marker after nerve injury. Morphological and functional alterations recovered with muscle re-innervation. Thus, we report here that nerve lesion induced changes in the basal activity and discharge modulation of HMNs, concurrent with the loss of afferent inputs. Nevertheless, we suggest that an increase in membrane excitability, reported by others, and in the proportion of low-threshold units, could serve to preserve minimal electrical activity, prevent degeneration and favour axonal regeneration.

Action Potentials↗