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Biomedical subjects

M A Haxhiu

Publications and source records attributed to M A Haxhiu.

At least 19 recordsLinked to original sources
PubMed2006

Stimulation of the hypothalamic paraventricular nucleus modulates cardiorespiratory responses via oxytocinergic innervation of neurons in pre-Botzinger complex.

Previously we reported that oxytocin (OT)-containing neurons of the hypothalamic paraventricular nucleus (PVN) project to the pre-Bötzinger complex (pre-BötC) region and phrenic motoneurons innervating the diaphragm (D). The aim of these studies was to determine pathways involved in PVN stimulation-induced changes in upper airway and chest wall pumping muscle activity. In addition, we determined the role of OT-containing neurons in the PVN in mediating increased respiratory output elicited by PVN stimulation. Neuroanatomical experiments, using pseudorabies virus (PRV) as a transneuronal tracer in C8 spinalectomized animals showed that PVN neurons project to hypoglossal motoneurons innervating the genioglossus (GG) muscle. Furthermore, microinjection of the PVN with bicuculline, a GABA(A) receptor antagonist, significantly increased (P < 0.05) peak electromyographic activity of GG (GG(EMG)) and of D(EMG), frequency discharge, and arterial blood pressure (BP) and heart rate. Prior injection of OT antagonist [d-(CH(2))(5),Tyr(Me)(2),Orn(8)]-vasotocin intracisternally or blockade of OT receptors in the pre-BötC region with OT antagonist l-368,899, diminished GG(EMG) and D(EMG) responses and blunted the increase in BP and heart rate to PVN stimulation. These data show that PVN stimulation affects central regulatory mechanisms via the pre-BötC region controlling both respiratory and cardiovascular functions. The parallel changes induced by PVN stimulation were mediated mainly through an OT-OT receptor signaling pathway.

Animals↗
PubMed2003

Hypercapnia-induced activation of brainstem GABAergic neurons during early development.

During early development, GABAergic mechanisms contribute to the regulation of respiratory timing in response to CO2. In 5-7 day old piglets, a double labeling technique was used to determine whether GABA-containing neurons are activated by normoxic hypercapnia (10% CO2, 21% O2, and 69% N2). The c-Fos gene encoded protein (c-Fos) was employed to localize CO2 activated cells within the piglet medulla oblongata. Parvalbumin was used as a marker for GABAergic neurons. In animals breathing room air, only scant c-Fos-like immunoreactive neurons were observed. A marked increase in c-Fos positive cells was induced after a 60 min exposure to hypercapnia. Colocalization studies revealed that hypercapnia significantly increased c-Fos expression in GABA-containing neurons in the medulla oblongata, especially in the ventral aspect of the medulla, within the Bötzinger region, the gigantocellular reticular nucleus, and the caudal raphe nuclei. Only a few double-labeled cells were observed within the nucleus tractus solitarius. Therefore, brainstem GABAergic neurons are part of the neural networks that respond to CO2 and may contribute to respiratory frequency responses to hypercapnia during early development.

Analysis of Variance↗
PubMed2002

Paraventricular oxytocin neurons are involved in neural modulation of breathing.

In this study, we determined the projections of oxytocin-containing neurons of the paraventricular nucleus (PVN) to phrenic nuclei and to the rostral ventrolateral medullary (RVLM) region, which is known to be involved in respiratory rhythm generation. Studies were also designed to determine oxytocin-receptor expression within the RVLM and the physiological effects of their activation on respiratory drive and arterial blood pressure. Oxytocin immunohistochemistry combined with cholera toxin B, a retrograde tracer, showed that a subpopulation of oxytocin-containing parvocellular neurons in the dorsal and medial ventral regions of the PVN projects to phrenic nuclei. Similarly, a subpopulation of pseudorabies virus-labeled neurons in the PVN coexpressed oxytocin after injection of pseudorabies virus, a transynaptic retrograde marker, into the costal region of the diaphragm. A subpopulation of oxytocin expressing neurons was also found to project to the RVLM. Activation of this site by microinjection of oxytocin into the RVLM (0.2 nmol/200 nl) significantly increased diaphragm electromyographic activity and frequency discharge (P < 0.05). In addition, oxytocin increased blood pressure and heart rate (P < 0.05). These data indicate that oxytocin participates in the regulation of respiratory and cardiovascular activity, partly via projections to the RVLM and phrenic nuclei.

Animals↗
PubMed2001

Peroxidases inhibit nitric oxide (NO) dependent bronchodilation: development of a model describing NO-peroxidase interactions.

Recent studies demonstrate that nitric oxide (NO) serves as a physiological substrate for mammalian peroxidases [(2000) J. Biol. Chem. 275, 37524]. We now show that eosinophil peroxidase (EPO) and lactoperoxidase (LPO), peroxidases known to be enriched in airways of asthmatic subjects, function as a catalytic sink for NO, modulating its bioavailability and function. Using NO-selective electrodes and direct spectroscopic and rapid kinetic methods, we examined the interactions of NO with EPO and LPO compounds I and II and ferric forms and compared the results to those reported for myeloperoxidase. A unified kinetic model for NO interactions with intermediates of mammalian peroxidases during steady-state catalysis is presented that accommodates unique features observed with each member of the mammalian peroxidase superfamily. Potential functional consequences of peroxidase-NO interactions in asthma are investigated by utilizing organ chamber studies with tracheal rings. In the presence of pathophysiologically relevant levels of peroxidases and H(2)O(2), NO-dependent bronchodilation of preconstricted tracheal rings was reversibly inhibited. Thus, NO interaction with mammalian peroxidases may serve as a potential mechanism for modulating their catalytic activities, influencing the regulation of local inflammatory and infectious events in vivo.

Animals↗
PubMed2001

Differential effects of hypercapnia on expiratory phases of respiration in the piglet.

Hypercapnia induces prolongation of expiratory time (TE) during early development. In the present study, we determined the response to steady state hypercapnia of three neural phases of the total respiratory cycle, inspiration (TI), stage 1 or passive expiration, TE-1 and stage 2 or active expiration, TE-2. Experiments were performed in decerebrate, vagotomized, spontaneously breathing piglets aged 5-10 days. Neural phases of the respiratory cycle were based on electrical activities of the thyroarytenoid (TA, laryngeal adductor) and triangularis sternii (TS, chest wall expiratory muscle) in relation to diaphragm (D) activity. We observed that hypercapnia induced prolongation of both expiratory phases. The greater prolongation of TE-1 was associated with an increase in TA activity and an increase in laryngeal resistance, which peaked early in TE-1, and then progressively decreased. These findings demonstrate that, in early postnatal life, a hypercapnia induced increase in respiratory drive is associated with centrally mediated prolongation of both phases of expiration, a greater prolongation of TE-1, and an increase in laryngeal resistance during post-inspiration. We speculate that the latter serves to optimize gas exchange by reducing large fluctuations in functional residual capacity.

Animals↗
PubMed2001

CNS innervation of posterior cricoarytenoid muscles: a transneuronal labeling study.

The CNS cell groups that project to neurons, which innervate the posterior cricoarytenoid muscles (PCA), were identified by the viral retrograde transneuronal labeling method. Pseudorabies virus (PRV) was injected into the PCA of C8 spinal rats and after 5 days survival, brain tissue sections were processed for immunohistochemical detection of PRV. Retrogradely labeled motor neurons innervating the PCA were seen in the nucleus ambiguus and in the area ventral to it. Neurons innervating the PCA motoneurons were found throughout the ventral aspect of the medulla oblongata, in the nucleus tractus solitarius, and in the pons. Labeling was present in the midbrain periaquaductal gray, in the lateral and paraventricular hypothalamic nuclei, in the amygdaloid complex, in the hippocampus, and within the piriform cortex. In summary, the motor neurons that control PCA activity are innervated predominantly by a network of neurons that lie along the neuraxis, in the regions known to be involved in regulation of respiratory output and autonomic functions.

Animals↗
PubMed2001

Monoaminergic neurons, chemosensation and arousal.

In recent years, immense progress has been made in understanding central chemosensitivity at the cellular and functional levels. Combining molecular biological techniques (early gene expression as an index of cell activation) with neurotransmitter immunohistochemistry, new information has been generated related to neurochemical coding in chemosensory cells. We found that CO(2) exposure leads to activation of discrete cell groups along the neuraxis, including subsets of cells belonging to monoaminergic cells, noradrenaline-, serotonin-, and histamine-containing neurons. In part, they may play a modulatory role in the respiratory response to hypercapnia that could be related to their behavioral state control function. Activation of monoaminergic neurons by an increase in CO(2)/H(+) could facilitate respiratory related motor discharge, particularly activity of upper airway dilating muscles. In addition, these neurons coordinate sympathetic and parasympathetic tone to visceral organs, and participate in adjustments of blood flow with the level of motor activity. Any deficit in CO(2) chemosensitivity of a network composed of inter-related monoaminergic nuclei might lead to disfacilitation of motor outputs and to failure of neuroendocrine and homeostatic responses to life-threatening challenges (e.g. asphyxia) during sleep.

Animals↗
PubMed2001

Reciprocal immunomodulatory effects of gamma interferon and interleukin-4 on filaria-induced airway hyperresponsiveness.

Tropical pulmonary eosinophilia (TPE) is a severe asthmatic syndrome of lymphatic filariasis, in which an allergic response is induced to microfilariae (Mf) in the lungs. Previously, in a murine model for TPE, we have demonstrated that recombinant interleukin-12 (IL-12) suppresses pulmonary eosinophilia and airway hyperresponsiveness (AHR) by modulating the T helper (Th) response in the lungs from Th2- to Th1-like, with elevated gamma-interferon (IFN-gamma) production and decreased IL-4 and IL-5 production. The present study examined the immunomodulatory roles of IL-4 and IFN-gamma in filaria-induced AHR and pulmonary inflammation using mice genetically deficient in these cytokines. C57BL/6, IL-4 gene knockout (IL-4(-/-)), and IFN-gamma(-/-) mice were first immunized with soluble Brugia malayi antigens and then inoculated intravenously with 200,000 live Mf. Compared with C57BL/6 mice, IL-4(-/-) mice exhibited significantly reduced AHR, whereas IFN-gamma(-/-) mice had increased AHR. Histopathologically, each mouse strain showed increased cellular infiltration into the lung parenchyma and bronchoalveolar space compared with naïve animals. However, consistent with changes in AHR, IL-4(-/-) mice had less inflammation than C57BL/6 mice, whereas IFN-gamma(-/-) mice had exacerbated pulmonary inflammation with the loss of pulmonary architecture. Systemically, IL-4(-/-) mice produced significantly higher IFN-gamma levels compared with C57BL/6 mice, whereas IFN-gamma(-/-) mice produced significantly higher IL-4 levels. These data indicate that IL-4 is required for the induction of filaria-induced AHR, whereas IFN-gamma suppresses AHR.

Animals↗
PubMed2001

Central GABAergic mechanisms are involved in apnea induced by SLN stimulation in piglets.

Stimulation of the superior laryngeal nerve (SLN) results in apnea in animals of different species, the mechanism of which is not known. We studied the effect of the GABA(A) receptor blocker bicuculline, given intravenously and intracisternally, on apnea induced by SLN stimulation. Eighteen 5- to 10-day-old piglets were studied: bicuculline was administered intravenously to nine animals and intracisternally to nine animals. The animals were anesthetized and then decerebrated, vagotomized, ventilated, and paralyzed. The phrenic nerve responses to four levels of electrical SLN stimulation were measured before and after bicuculline. SLN stimulation caused a significant decrease in phrenic nerve amplitude, phrenic nerve frequency, minute phrenic activity, and inspiratory time (P < 0.01) that was proportional to the level of electrical stimulation. Increased levels of stimulation were more likely to induce apnea during stimulation that often persisted beyond cessation of the stimulus. Bicuculline, administered intravenously or intracisternally, decreased the SLN stimulation-induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency (P < 0.05). Bicuculline also reduced SLN-induced apnea and duration of poststimulation apnea (P < 0.05). We conclude that centrally mediated GABAergic pathways are involved in laryngeal stimulation-induced apnea.

Animals↗
PubMed2001

Nitric oxide deficiency contributes to impairment of airway relaxation in cystic fibrosis mice.

The pulmonary disease of cystic fibrosis (CF) is characterized by persistent airway obstruction, which has been attributed to chronic endobronchial infection and inflammation. The levels of exhaled nitric oxide (NO) are reduced in CF patients, which could contribute to bronchial obstruction through dysregulated constriction of airway smooth muscle. Because airway epithelium from CF mice has been shown to have reduced expression of inducible NO synthase, we examined airway responsiveness and relaxation in isolated tracheas of CF mice. Airway relaxation as measured by percent relaxation of precontracted tracheal segments to electrical field stimulation (EFS) and substance P, a nonadrenergic, noncholinergic substance, was significantly impaired in CF mice. The airway relaxation in response to prostaglandin E2 was similar in CF and non-CF animals. Treatment with the NO synthase inhibitor NG-nitro-L-arginine methylester reduced tracheal relaxation induced by EFS in wild-type animals but had virtually no effect in the CF mice. Conversely, exogenous NO and L-arginine, a NO substrate, reversed the relaxation defect in CF airway. We conclude that the relative absence of NO compromises airways relaxation in CF, and may contribute to the bronchial obstruction seen in the disease.

Animals↗
PubMed2000

The excitatory amino acid glutamate mediates reflexly increased tracheal blood flow and airway submucosal gland secretion.

In six decerebrated and in eight alpha-chloralose anesthetized, paralyzed and mechanically ventilated beagle dogs, we have studied involvement of glutamate and glutamate receptors in transmission of excitatory inputs from the airway sensory receptors to the nucleus tractus solitarius and from this site to airway-related vagal preganglionic cells that regulate the tracheal circulation and the submucosal gland secretion. Stimulation of airway sensory fibers by lung deflation-induced reflex increase in tracheal blood flow and submucosal gland secretion. These responses were diminished by prior administration of AMPA/kainate receptor antagonist CNQX into the fourth ventricle (n=6). Furthermore, topical application or microinjection of AMPA/kainate receptor blockers, into the region of the ventrolateral medulla, where airway-related vagal preganglionic neurons are located, abolished the reflex changes in tracheal submucosal gland secretion (n=8); in these dogs mucosal blood flow was not measured). These findings indicate that reflex increase in tracheal blood flow and submucosal gland secretions are mediated mainly via release of glutamate and activation of the AMPA/kainate subtype of glutamate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

The alpha3 subtype of the nicotinic acetylcholine receptor is expressed in airway-related neurons of the nucleus tractus solitarius, but is not essential for reflex bronchoconstriction in ferrets.

To assess the role of nicotinic acetylcholine receptors (nACh-R) in the transmission of afferent constricting inputs from bronchopulmonary receptors to the nucleus tractus solitarius (nTS) and in the mediation of reflex airway constriction, we performed a combined immunohistological and functional study. In ferrets, the expression of nAch-R on the nTS neurons activated by histamine stimulation of airway sensory receptors was studied using laser scanning confocal microscopy to co-immunolocalize c-fos encoded protein (cFos) and nACh-R alpha3 subunit. We observed that activation of airway sensory receptors by inhalation of aerosolized histamine, induced cFos expression in a subset of nTS neurons that also expressed the nAch-R alpha3 subtype. Furthermore, activation of nACh-R within the commissural subnucleus by nicotine, increased cholinergic outflow to the airways. These effects were diminished by prior administration of hexamethonium (nACh-R blocker) within the commissural subnucleus of the nTS. However, hexamethonium had no significant effects on airway reflex constrictions induced by lung deflation. These findings indicate that nACh-R are expressed by the nTS neurons receiving inputs from airway sensory receptors, activation of which by nicotine increases cholinergic outflow to the airways, but the nACh-R pathways are not required for reflex bronchoconstriction.

Airway Resistance↗
PubMed2000

alpha(2)-adrenergic receptors are not required for central anti-hypertensive action of moxonidine in mice.

In the mouse medulla oblongata, we characterized binding properties and functional responses of two recognition sites for imidazoline compounds: I(1)-imidazoline and alpha(2)-adrenergic receptors. The mouse medulla expresses a higher density of I(1)-receptors than in the rat, whereas alpha(2)-receptor densities were similar between the two species. In anesthetized, ventilated and paralyzed mice, we tested the hypotensive actions of the I(1)/alpha(2) agonist moxonidine, determined its central site of its actions, and the relative roles of I(1) and alpha(2)-receptors. Experiments were performed in C(57)Bl(6) wild type and alpha(2A)-adrenergic receptor deficient mice. In both types of mice, neuronal activation within the rostral ventrolateral medulla (RVLM) region by glutamate microinjection elicited increases in arterial pressure. Moxonidine (0.5 nmol/site/10 nl) microinjected bilaterally into this vasopressor region decreased arterial pressure by 30% and heart rate by 11% in wild type mice. Efaroxan, the I(1)/alpha(2) antagonist (0.4 nmol) when microinjected into the RVLM elevated blood pressure itself and abolished the action of moxonidine, whereas alpha(2)-blockade with SK&F 86466 had no significant effect on blood pressure and did not attenuate moxonidine's effect. To more definitively test the role of alpha(2)-adrenergic receptors in the action of moxonidine, moxonidine was microinjected into the RVLM of alpha(2A)-adrenergic deficient mice. The decreases in arterial pressure were nearly identical to those of wild type mice, whereas bradycardia was attenuated. Thus, in the mouse moxonidine acts within the RVLM region to lower arterial pressure mainly through the I(1)-imidazoline receptor independent of alpha(2)-adrenergic receptors.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Involvement of glutamate in transmission of afferent constrictive inputs from the airways to the nucleus tractus solitarius in ferrets.

In this study, we identified the neurons within nucleus tractus solitarius (nTS) activated by stimulation of airway sensory systems and examined the expression of AMPA receptor subtype(s) by these cells. We also investigated the possible involvement of endogenously released glutamate and AMPA receptors in the transmission of excitatory inputs from the sensory system of the respiratory tract to the neurons of the nTS. In these experiments we used: (1) immunodetection of c-fos encoded protein (cFos) expression to identify the nTS neurons activated by the stimulation of the airway sensory system; (2) receptor immunochemistry and confocal microscopy to determine the receptor(s) expressed by activated nTS neurons; (3) microdialysis to measure glutamate release, and (4) physiological measurements to examine the effects of selective receptor blockers, and thereby define the role of the glutamate and AMPA glutamatergic receptor subtype(s) in reflexly induced airway constriction. The results showed that activation of airway sensory receptors, by inhalation of aerosolized histamine or capsaicin, induced cFos expression in a subset of nTS neurons that also expressed the AMPA subtype of glutamate receptors. Furthermore, activation of sensory bronchoconstrictive receptors induced glutamate release within nTS, and blockade of the AMPA receptor subtype within nTS inhibited reflexly increased cholinergic outflow to the airways. These data indicate for the first time that glutamate and AMPA receptor signaling pathways are involved in the transmission of afferent inputs from the airways to the nTS, and in mediating reflex airway constriction.

Aerosols↗
PubMed2000

Recurrent hypoxic exposure and reflex responses during development in the piglet.

The effects of recurrent hypoxia on cardiorespiratory reflexes were characterized in anesthetized piglets at 2-10 d (n=15), 2-3 weeks (n=11) and 8-10 weeks (n=8). Responses of phrenic and hypoglossal electroneurograms (ENG(phr) and ENG (hyp)) to hypoxia (8% 0(2), bal N(2), 5 min), hypercapnia (7% CO(2) bal O(2), 5 min) and intravenous capsaicin were tested before and after recurrent exposure to 11 episodes of hypoxia (8% O(2) bal N(2), 5 min). In piglets 2-10 d, ENG(phr) response to hypoxia declined in proportion to the number of hypoxic exposures; however, ENG (hyp) response to hypoxia was unchanged. In piglets at 2-10 d, intracisternal injection of bicuculline (GABA(A) receptor antagonist) reversed effects of recurrent hypoxia on ENG(phr) hypoxic response, eliminated apnea during hypoxia, as well as the delay in appearance of ENG(phr) after hypoxia. The ENG(phr) response to 7% CO(2) inhalation also decreased after recurrent hypoxia; however, the ENG(phr) response to C-fiber stimulation by capsaicin was unaltered. Piglets at 2-3 and 8-10 weeks were resistant to the depressive effects of recurrent hypoxia on respiratory reflex responses. We conclude that the response of the anesthetized newborn piglet to recurrent hypoxia is dominated by increasing inhibition of phrenic neuroelectrical output during successive hypoxic exposures. Central GABAergic inhibition may contribute significantly to the cumulative effects of repeated hypoxia in the newborn piglet experimental model.

Animals↗
PubMed2000

Closed-loop stimulation of hypoglossal nerve in a dog model of upper airway obstruction.

Electrical stimulation of upper airway (UAW) muscles has been under investigation as a treatment method for obstructive sleep apnea (OSA). Particular attention has been given to the electrical activation of the genioglossal muscle, either directly or via the stimulation of the hypoglossal nerve (HG), since the genioglossus is the main tongue protrusor muscle. Regardless of the stimulation site or method, an implantable electrical stimulation device for OSA patients will require a reliable method for detection of obstructive breaths to apply the stimulation when needed. In this paper, we test the hypothesis that the activity of the HG nerve can be used as a feedback signal for closed-loop stimulation of the HG nerve in an animal model of UAW obstruction where a force is applied on the submental region to physically narrow the airways. As an advantage, the method uses a single electrode for both recording and stimulation of the HG nerve. Simple linear filtering techniques were found to be adequate for producing the trigger signal for the electrical stimulation from the HG recordings. Esophageal pressure, which was used to estimate the size of the UAW passage, returned to the preloading values during closed-loop stimulation of the HG nerve. The data demonstrate the feasibility of the closed-loop stimulation of the HG nerve using its activity as the feedback signal.

Airway Obstruction↗
PubMed2000

Differential cardiorespiratory control elicited by activation of ventral medullary sites in mice.

We studied the respiratory and blood pressure responses to chemical stimulation of two regions of the ventral brainstem in mice: the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively). Stimulation of the RVLM by microinjections of the excitatory amino acid L-glutamate induced increases in diaphragm activity and breathing frequency, elevation of blood pressure (BP), and a slight increase in heart rate (HR). However, activation of the CVLM induced a decrease in breathing frequency, mainly due to prolongation of expiratory time (TE), and hypotension associated with a slight slowing of HR. Because adrenergic mechanisms are known to participate in the control of respiratory timing, we examined the role of alpha(2)-adrenergic receptors in the RVLM region in mediating these inhibitory effects. The findings demonstrated that blockade of the alpha(2)-adrenergic receptors within the RVLM by prior microinjection of SKF-86466 (an alpha(2)-adrenergic receptor blocker) significantly reduced changes in TE induced by CVLM stimulation but had little effect on BP responses. These results indicate that, in mice, activation of the RVLM increases respiratory drive associated with an elevation of BP, but stimulation of CVLM induces prolongation of TE via an alpha(2)-adrenergic signal transduction pathway.

Adrenergic alpha-2 Receptor Antagonists↗