J F Paton

..Thus, inflammatory reactions in the brain stem are causally associated with neurogenic hypertension...

..In conclusion, carotid sinus nerve inputs from the carotid body are, in part, responsible for elevated sympathetic tone and critical for the genesis of hypertension in the developing SHR and its maintenance in later life...

..We have evaluated this issue using a tetracycline (Tet)-controllable and cell-specific miRNA 30 (miR30)-based short hairpin (shRNA) interference system...

..Originally TAS involved the use of two copies of a cell-specific promoter leading to generation of large expression cassettes, which can be hard to use given the space limitations of the conventional viral gene expression vectors...

..If we are correct, future successful treatment of essential hypertension in man will include methods of reducing cerebral arterial resistance...

..The present study supports the novel concept that AngII can trigger NO release in the NTS by a mechanism of vascular-neuronal signalling that affects central neuronal networks regulating cardiovascular function...

..We propose that eNOS-generated NO in the SHR may be a compensatory mechanism for any potential threat to an adequate blood supply to the brain (eg, from genetically small arteries supplying the brainstem)...

..Based on these data, we predict that periods of prolonged hypoxia, such as those that occur during sleep apnoeas, will constrain inspiratory glottic abduction thereby impeding inhalation...

..We speculate on why eNOS activity may be up regulated in the NTS of the SHR and propose that it is a consequence of high cerebral vascular resistance and inadequate blood perfusion of the brainstem...

..High brainstem vascular resistance and its inflammation may release pathological paracrine signaling molecules affecting central neural cardiovascular activity conducive to neurogenic hypertension...

..Our findings have led us to hypothesize a novel form of intercellular communication within the NTS, one of vascular-neuronal signaling...

..This may be important when pumping blood into a constricted vascular tree, such as is the case during the peripheral chemoreceptor reflex and the diving response...

..Modulation of such conductances during either physiological (exercise) or pathophysiological (essential hypertension) conditions may lead to changes in both the operating point and gain of the baroreceptor reflex...

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..We provide evidence for hypoxia-driven transformation within the central respiratory oscillator, in which gasping relies on persistent sodium current, whereas eupnea does not depend on this cellular mechanism...

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..Endothelial cells were also double labelled for eNOS and AT1 receptors. We suggest that ANGII activates eNOS located in either neurones and/or endothelial cells to release NO, which acts selectively to depress the baroreflex...

..The possibility of a mutual inhibitory interaction between PreI and PI neurones is discussed in terms of the functional organization of the respiratory network in the mouse...

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..In summary, this study provides new data on the neurophysiological, anatomical and morphological properties of nucleus of the solitary tract neurones responding to arterial chemoreceptors in the rat...

..It is suggested that this rhythmic bursting depends on inhibitory connections from PreI neurones. The functional significance of these central 'apnoeic rhythms' are discussed...

..The specific convergence pattern of baroreceptors and chemoreceptors to these cardioreceptive NTS neurones is discussed in relation to a common afferent modality integration within the NTS...

..The balance of these actions of ANGII could be reflex specific: for the baroreflex circuitry the inhibitory action might predominate while the peripheral chemoreceptor reflex may be facilitated due to enhanced excitatory transmission...

..These data support a selective involvement of NK1 receptors in the transmission of cardiac vagal afferent inputs to NTS neurons integrating cardiorespiratory information...

..An AT2-antagonist, PD123-319 did not restore the BVR sensitivity in pre-weaned rats. Thus, AT1 receptors located within the NTS play a pivotal role in the developmental attenuation of the BVR in pre-weaned rats...

..Our observations lend further support to models of cardiorespiratory control which propose close coupling and shared central mechanisms for the regulation of the cardiovascular and respiratory systems...

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..It is concluded that the qualitatively similar reflex performances between the in vivo anaesthetised mouse and the WHBP make the latter an adequate model for studying central mechanisms controlling the cardiorespiratory system...

..We conclude that the neonatal rat WHBP is an in situ preparation because it produces a respiratory rhythm similar to that of adult in vivo mammal preparations but distinct from in vitro preparations...

..We suggest that our data may have clinical implications relating to hypertension, a condition when angiotensin II activity is heightened in the brain and the efficacy of the baroreflex is reduced...

..This differential sensitivity of excitatory and inhibitory connections to NO may be important for determining the specificity of the effects of this freely diffusible gaseous messenger...

..p.m., n = 4, P < 0.05). Gene transfer did not affect arterial pressure. These findings suggest that in the conscious rat eNOS is constitutively active within the NTS and is a factor regulating baroreceptor reflex gain and heart rate...

..These data have relevance to patients with essential hypertension and left heart failure, conditions in which ANGII activity is elevated and the baroreceptor reflex is depressed...

..The WH-BP may provide an advantaged environment for analysis of both synaptic and cellular mechanisms within the medulla that regulate cardio-respiratory activity...

..We conclude that viable WHBP can be prepared from Suncus and that Suncus WHBP is a novel non-rodent model in which to study brainstem-mediated reflexes...

..The lecture attempts to demonstrate why this is important for enhancing the functional significance and relevance of physiological data as well as for validating predictions...

..We propose that neurones in raphe pallidus that project to the NTS can release serotonin which acts via 5-HT4 receptors to attenuate the reflex phrenic nerve activity and heart rate components of the cardiopulmonary reflex...

..It appears that anesthesia does not block the sympathoexcitatory response but acts to augment sympathoinhibitory processes associated with uvula stimulation; some possible mechanisms are discussed...

..We conclude that the use of adenoviruses to manipulate genes offers a new avenue for physiologists studying neuronal mechanisms in integrative models...

..In the WHBP, NTS neurones appear important for mediating the cardiac component of the reflex response following stimulation of nociceptive reflex pathways...

..Thus, endogenous eNOS activity in the NTS plays a major role in determining the set point of arterial pressure in the SHR and contributes to maintaining high arterial blood pressure in this animal model of human hypertension...

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..In contrast, multiple site disruption of a pathway leading to eNOS activation via the serine/threonine kinase Akt was ineffective..

..This is the first demonstration of a possible physiological impact of the epsilon-subunit on native GABA(A) receptors...

..In Goldblatt hypertension, superoxide signaling in the RVLM plays a major role in the generation of sympathetic vasomotor tone and the chronic sustained hypertension in this animal model...

..Further longitudinal studies are required to determine whether these alterations play a role in the increased risk of late hypertension in these patients...

..When JAM-1 is expressed in the nucleus tractus solitarii, it raises arterial pressure, suggesting a novel prohypertensive role for this protein within the brain stem...

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..7+/-0.07 to 0.5+/-0.04 ms/mm Hg; P<0.001) in the SHRs. Thus, PI3K signaling in the nucleus tractus solitarii of SHR restrains arterial pressure in this animal model of neurogenic hypertension...

..01). We conclude that 1) somatic brachial and PAG afferents can converge onto single NTS neurons; 2) this convergence occurs via either direct or indirect pathways; and 3) NK(1) receptors are activated by some of these inputs...

..Both effects could contribute to elevated sympathetic activity and blood pressure in the spontaneously hypertensive rat...

..This effect is highly selective in that the chemoreceptor afferent-evoked tachypnoea, as well as other visceral receptor-mediated reflex bradycardia, remain unaffected...

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..The choice of the mouse will furthermore permit studies to be performed on genetically mutant strains...

..Moreover, we have confirmed its versatility by demonstrating its application to man...

..The study tested the hypothesis that systemic bupivacaine has toxic effects on brainstem cardiorespiratory control...

..We aimed to genetically target A2 neurons and induce expression of a potassium channel to reduce their electrical excitability and study how this impacts on long-term blood pressure control...

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..We conclude that nociceptive afferents activate NK1 receptors, which in turn excite GABAergic interneurons impinging on cells mediating the cardiac component of the baroreceptor reflex...

..Thus the NTS integrates information from corneal receptors, some of which converges onto neurons mediating reflexes from baroreceptors and chemoreceptors to inhibit these inputs...

..Thus, the NO-cGMP-cADPR-Ca2+ pathway, previously described in sea urchin eggs, also operates in mammalian GABAergic neurons. Potentiation of GABA release by NO may have implications for numerous brain functions...

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..The decerebrate, artificially-perfused rat (DAPR) provides a powerful methodology with which to study peripheral and central control of the autonomic nervous system with many of the benefits of an in vitro environment...

..Finally, analysis of these 'hypertension-related' elements revealed genes that are involved in the regulation of both blood pressure and immune function and as such are excellent targets for further study...

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..This altered neurochemistry within the LHA further highlights the potential importance of nitric oxide and the LHA in central regulation of fluid homeostasis...

..Further, these findings confirm that baroreflex sympathetic and parasympathetic pathways diverge, and can be independently controlled, within the NTS...

..05). We propose that MIF acting within the PVN is a major counterregulator of HS-induced sympathoexcitation, an effect that depends on thiol-protein oxidoreductase activity...

..The functional interpretation we propose is that by depressing homeostatic reflexes at the NTS, noxious stimulation-evoked cardiorespiratory changes can be expressed and maintained, which may be essential for the survival of the animal...

..Thus, the present study provides compelling evidence that VSVG-coated LVVs significantly shift transgene expression towards neurones while transduction with AVVs favours glia...

..The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome...

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..Indeed, our results establish that hypoglossal discharge alone is an equivocal index of the pattern of overall ventilatory activity and that this is accentuated by hypercapnia and hypothermia...

..The effect of blocking glycine receptors was the same in both mature and newborn rats suggesting that glycinergic inhibition is essential for co-ordinating cranial and spinal motor outputs from birth...

..We conclude that the neurogenesis of gasping is not dependent upon fast, chloride-mediated inhibitory synaptic transmission...

..Thus the integrity of glycinergic inhibition within the pontomedullary respiratory network is critical for the coordination of cranial and spinal motor outflows during eupnea but also for protective reflex regulation of the upper airway...

..Results are consistent with the concept that the elicitation of gasping represents a switch from a network-based rhythmogenesis for eupnea to a pacemaker-driven mechanism...

..Thus, CIH alters the coupling between the central respiratory generator and sympathetic networks that may contribute to the induced hypertension in this experimental model...

..These data show that the AT1R in the spinal cord is ideally located to influence autonomic outflow and hence participate in the CNS determination of blood pressure...

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..The latter is of clinical interest, because this may relate to the finding of cot death victims who died as a result of upper airway obstruction but without apparent apnea or rebreathing...

..Evidence from previous studies that support the validity of these criteria is presented herein. We conclude that pontile mechanisms play a critical role in the neurogenesis of eupnea...

..The method is reproducible and can be scaled up to facilitate the use of these vectors in animal studies...

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..These administrations did cause sedation. We conclude that conductance through persistent sodium channels plays little role in the neurogenesis of eupnea...

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..These findings are discussed in the context of the role of endogenous bursting activity in the respiratory rhythm generation in vivo vs. in vitro and during normal breathing in vivo vs. gasping...

..We propose that neural mechanisms within the cervical-thoracic segments can make a substantial contribution to the sympathoexcitatory response during systemic ischaemia...

..We conclude that glutamatergic and purinergic mechanisms are part of the complex neurotransmission system of the sympathoexcitatory component of the chemoreflex at the level of the commissural NTS...

..This discharge peaked at the onset of the gasp and then decremented during neural inspiration. We hypothesize that these 'pre-inspiratory' neuronal activities generate the gasp by intrinsic pacemaker mechanisms...

..0001). We conclude that the emetic reflex can be activated in our Suncus preparations and that this non-sentient small adult animal model can now be used to study the neurophysiology and pharmacology of swallowing and emesis...

..The model predicts a continuum of respiratory network states relying on different contributions of intrinsic cellular properties versus synaptic interactions for the generation and control of the respiratory rhythm and pattern...

..both bradycardia and sympathoinhibition) was abolished after pontine removal. We propose that neural activity of the pons is essential for physiological coupling of centrally generated respiratory and cardiovascular efferent activities...