Carotid baroreceptors are mainly localized in the medial portions of the proximal internal carotid artery.

AIM: To visualize baroreceptors in the human carotid bifurcation by light microscopy. Baroreceptor location is investigated in order to provide recommendations for the extent of adventitial stripping in the treatment for carotid sinus syndrome (CSS). METHODS: Human carotid specimens were transversely cut in 20 µm sections. After immunohistochemical staining using antibodies to vesicular glutamate transporter 2 (VGLUT2) and protein gene product 9.5 (PGP 9.5), the presence of baroreceptor tissue was studied using light microscopic techniques. RESULTS: Visual assessment indicated that VGLUT2 and PGP 9.5 immunoreactivity was present in the adventitia of the carotid arteries and that nerve density was highest in the medial wall of the proximal first cm of the internal carotid artery (ICA). CONCLUSION: Human carotid baroreceptors, as reflected in immunoreactivity for VGLUT2 and PGP 9.5, are mainly localized in the medial portions of the proximal ICA. If surgical carotid denervation is indicated in patients suffering from carotid sinus syndrome, adventitial stripping of the proximal portion of the ICA should be sufficient.

Cineantropometría: Composición corporal y somatotipo de futbolistas que desarrollan su actividad física en equipos de la Comunidad Autónoma de Madrid / Kinanthropometry: Body composition and somatotype of football players whose physical activity is performed in teams of the Autonomous Region of Madrid

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DOPA causes glutamate release and delayed neuron death by brain ischemia in rats.

DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.

Central administration of neuropeptide FF (NPFF) causes increased neuronal activation and up-regulation of NPFF gene expression in the rat brainstem.

Neuropeptide FF (NPFF) is a morphine modulatory peptide that plays an important role in a wide variety of physiological functions, including those related to nociception and central autonomic regulation. NPFF fibers and cells have been shown to be discretely localized in key autonomic centers within the brain, including the brainstem nucleus of the solitary tract (NTS). Central applications of NPFF evoke a number of important biological effects through activation of central neuronal circuits whose identities remain unknown at present. NPFF administered in this manner may also be capable of up- or down-regulating its own gene expression. In this study, we investigated the effects of intracerebroventricular (i.c.v.) administration of NPFF on the activation and the gene expression of NPFF in NTS neurons. Conscious rats received saline or NPFF (8 or 10 microg i.c.v.), with concomitant monitoring of arterial blood pressure. Brains were prepared for Fos immunohistochemistry to identify neuronal activation and NPFF in situ hybridization to determine cells expressing NPFF mRNA in the NTS. At a dose of 8 microg, i.c.v., NPFF did not evoke alterations in blood pressure, but, at 10 microg, there was an increase in arterial blood pressure of 30-40 mmHg. Image analysis showed a dose-dependent increase in number of NPFF neurons that were activated in rats receiving i.c.v. NPFF compared with saline controls. NPFF gene expression in the NTS showed a similar dose-dependent increase following i.c.v. administration of either 8 or 10 microg of NPFF. Significantly greater numbers of activated neurons expressing the NPFF gene (double labeled) were observed in the NTS at the level of the area postrema in animals receiving i.c.v. NPFF compared with saline controls. These data indicate that centrally administered NPFF is capable of up-regulating its own gene expression in the NTS and that this effect appears in part to be independent of elevations in arterial blood pressure that this peptide can evoke when administered i.c.v. at the higher dose. The up-regulation of NPFF may play a homeostatic role in response to specific cardiovascular challenges, such as hypotension.

The direct effect of insulin on barosensitive neurones in the nucleus tractus solitarii of rats.

The present investigation was designed to determine the direct effect of insulin on the spontaneous discharge of barosensitive neurones in the nucleus tractus solitarii (NTS) of rats anaesthetized with urethane. Microinjection of 20 nl insulin (10 IU/ml) into NTS decreased the spontaneous discharge of 38 of the 52 units studied (73.1%), and this decrease was augmented by increasing the concentration to 40 IU/ml. Microinjections of insulin vehicle, glucose, hydralazine or phenylephrine did not elicit significant changes in the spontaneous discharge of NTS barosensitive neurones. These results demonstrate that insulin inhibits the spontaneous discharge of barosensitive NTS neurones. They suggest that insulin increases sympathetic nervous activity via a central neural mechanism and may play a role in the modulation of cardiovascular information within the NTS.

Sciatic and vagal sensory inputs converge onto non-baroreceptive neurones of the rostral ventrolateral medulla.

Previous data suggested that somatic and vagal sensory afferent inputs may converge in the rostral ventrolateral medulla oblongata (RVLM). The aim of the present study was to establish the existence of convergence between inputs mediated via the cervical vagus and contralateral sciatic nerves using in vivo intracellular recordings. The majority of RVLM neurones that received input from the vagus or the sciatic nerves also responded to stimulation of the other nerve. In 72% of the neurones the response was excitation or inhibition to stimulation of both nerves, respectively. The most frequent response type was a short excitation in response to stimulation of both nerves. Only 8% of the neurones exhibited a visible response to stimulation of the aortic depressor nerve. The results provided experimental evidence that non-baroreceptive neurones of the RVLM are involved in coordination of somatic and visceral sensory inputs.

Pharmacological activation of nociceptin receptors in the nucleus tractus solitarius inhibits baroreceptor reflex in pentobarbital-anesthetized rats.

Nociceptin receptors are densely distributed in the nucleus tractus solitarius pre- and postsynaptically. This study tested whether nociceptin receptors in this brain area are involved in the modulation of baroreceptor reflex. In pentobarbital-anesthetized rats, pharmacological activation of nociceptin receptors with bilateral microinjection of a synthetic peptide agonist, nociceptin, into the nucleus tractus solitarius attenuated baroreflex sensitivity as demonstrated by a marked reduction in baroreflex bradycardia induced by a single dose of intravenous phenylephrine. The inhibitory effect of nociceptin was dose dependent (0.04, 0.2 and 1nmol) and was blocked by pretreatment with microinjection of 1nmol nocistatin, a peptide that can functionally reverse the action of nociceptin. In contrast, injection of an opioid receptor antagonist, naloxone (5nmol), did not modify the inhibition of baroreflex sensitivity induced by nociceptin. Neither nocistatin nor naloxone injected into the nucleus alone had any detectable effect on baseline blood pressure and heart rate and baroreflex bradycardia. These data indicate that the newly discovered nociceptin receptors in the central nervous system possess an inhibitory influence on baroreflex transmission at the level of the nucleus tractus solitarius.

Effects of selective sinoaortic denervations on phenylephrine-induced activational responses in the nucleus of the solitary tract.

Intravenous administration of phenylephrine provokes a pattern of cellular activation in the nucleus of the solitary tract that resembles the central distributions of primary baroreceptor afferents supplied by the carotid sinus and aortic depressor nerves. Transganglionic transport and denervation methods were used in an experimental setting to test the dependence of phenylephrine-induced Fos immunoreactivity on the integrity of buffer nerve afferents, and to identify the subregions of the nucleus of the solitary tract supplied by each. Cholera toxin B-horseradish peroxidase injections into either or both nerves revealed terminal labeling concentrated in, but not restricted to, the dorsal commissural part of the nucleus of the solitary tract at the level of the apex of calamus scriptorius, and extending into the dorsal subnucleus at the level of the area postrema. Preferential ramifications of carotid sinus and aortic depressor nerve afferents at the levels of the commissural part of the nucleus and the area postrema, respectively, were reflected in the extent to which labeled fibers comingled with neurons exhibiting phenylephrine-induced Fos in dual labeling experiments. Complete sinoaortic denervation reduced by 90% the number of neurons exhibiting drug-induced Fos expression. Selective carotid and aortic sinus denervations effected partial reductions manifest preferentially in the caudal and rostral foci of the distribution, respectively. Reduced activational responses at the level of the area postrema of aortic sinus-denervated rats were accompanied by a reduction in cellular nicotinamide adenine dinucleotide phosphate-diaphorase activity in this region. Animals killed 30 days after complete sinoaortic denervation displayed no evidence of recovery of phenylephrine-induced Fos, while the strength and distribution of the response in rats that received selective carotid sinus denervation were indistinguishable from those seen in controls. These findings (i) support the dependence of phenylephrine-induced Fos expression on the integrity of carotid sinus and aortic depressor nerve afferents, (ii) provide anatomical and functional evidence that the two buffer nerves distribute differentially within the nucleus of the solitary tract, and (iii) implicate central reorganization as a likely basis for functional recovery of baroreflex mechanisms following partial sinoaortic denervation.

Differential regulation of the oscillations in sympathetic nerve activity and renal blood flow following volume expansion.

Renal sympathetic nerve activity (RSNA) and renal blood flow (RBF) both show oscillations at various frequencies but the functional significance and regulation of these oscillations is not well understood. To establish whether the strength of these oscillations is under differential control we measured the frequency spectrum of RSNA and RBF following volume expansion in conscious rabbits. Seven days prior to experiment animals underwent surgery to implant an electrode for recording renal nerve activity and a flow probe for recording RBF. Volume expansion (Haemaccel, 1.5 ml min(-1) kg(-1) for 15 min) resulted in a 25 +/- 5% decrease in mean RSNA, paralleled by an increase in RBF to 60 +/- 12 ml min(-1) from resting levels of 51 +/- 11 ml min(-1). Renal denervated rabbits did not show an increase in RBF with volume expansion. Arterial baroreflexes were unaltered by volume expansion. Spectral analysis of the different frequencies in RSNA showed oscillations in RSNA between 0.2 and 0.4 Hz were selectively decreased following volume expansion (14 +/- 3 to 6 +/- 1% of total power in RSNA at < 3 Hz). A corresponding decrease in the strength of oscillations in RBF at this frequency was also seen (20 +/- 6 to 8 +/- 2%). In contrast, the strength of respiratory (0.8-2.0 Hz) and cardiac (3-6 Hz) related rhythms did not change with volume expansion. These results show that selective changes in the different frequency components of RSNA can occur. We suggest that input from cardiopulmonary receptors and/or other vascular beds, and/or altered vascular resistance after volume expansion can reduce the strength of the 0.3 Hz oscillation independent of changes in arterial baroreflex control of RSNA.

Modulation of the carotid baroreceptor reflex by substance P in the nucleus tractus solitarius.

Previous studies have shown that administration of substance P (SP) into the nucleus tractus solitarius (NTS) can evoke a depressor response similar to that produced by activation of the arterial baroreceptors. In addition, some studies have suggested that SP increases the reflex responses to activation of baroreceptor input. The present study was performed to determine the effects of SP on the carotid sinus baroreceptor reflex at the level of the NTS by examining the effects of both exogenous SP microinjected into different rostrocaudal locations in the NTS and blockade of the effects of endogenous SP, through the microinjection of a substance P antagonist (SPa; [D-Pro, D-Trp]-substance P). Changes in pressure in an isolated carotid sinus in anesthetized dogs were used to evoke baroreflex changes in arterial blood pressure (BP) before and after microinjection of SP (0.5 microM) or SPa (10 microM) into barosensitive regions of the NTS. Microinjection of SP or its antagonist did not alter baseline, resting BP but did produce significant changes in baroreflex sensitivity. Microinjection of SP into different rostrocaudal regions of the NTS produced different responses, with rostral and caudal NTS microinjections producing significant increases in sensitivity. No effects on baroreflex sensitivity were obtained in response to SP microinjections into the intermediate NTS. Unlike SP, microinjection of the SPa significantly decreased baroreflex sensitivity at all rostrocaudal levels of the NTS. These data demonstrated that SP has the capability to modulate the carotid baroreflex at the level of the NTS and support a physiological role for endogenously released SP.

Release of glutamate and GABA in the amygdala of conscious rats by acute stress and baroreceptor activation: differences between SHR and WKY rats.

To reveal the functional importance of amino acid neurotransmission in the amygdala (AMY) of conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, the in vivo release of glutamate (GLU) and GABA in this brain structure was studied using the push-pull superfusion technique. Basal GLU and GABA release rates in the AMY were comparable in SHR and WKY rats, although arterial blood pressure (BP) in SHR (152+/-6 mmHg) was higher than in WKY rats (102+/-4 mmHg). Neuronal depolarization by superfusion with veratridine enhanced the release of GLU and GABA to a similar extent in both rat strains. On the other hand, exposure to noise stress (95 dB) for 3 min led to a tetrodotoxin-sensitive increase in GLU release in the AMY of SHR, but not WKY rats. The concurrent pressor response to noise was enhanced in SHR as compared to WKY rats. A rise in BP induced by intravenous infusion of phenylephrine for 9 min had no effect on amino acid release in the AMY of both strains. The data suggest an exaggerated stress response of glutamatergic neurons in the AMY of SHR as compared with WKY rats, which might be of significance for the strain differences in the cardiovascular and behavioural responses to stress. The results also show that, in both rat strains, glutamatergic and GABAergic neurons in the AMY are not modulated by baroreceptor activation. Moreover, hypertension in adult SHR does not seem to be linked to a disturbed synaptic regulation of glutamatergic or GABAergic transmission in the AMY.

Enhanced serotonin-mediated responses in the nucleus tractus solitarius of spontaneously hypertensive rats.

Previous studies have demonstrated that injection of serotonin into the nucleus tractus solitarius (NTS) elicits hypotension and bradycardia in rats. The present study sought to further characterize this response and to examine the role of serotonergic mechanisms in the NTS in cardiovascular regulation in spontaneously hypertensive (SHR) rats. Injections of picomole amounts of serotonin into the NTS of chloralose-anesthetized normotensive Sprague-Dawley (S-D) or Wistar-Kyoto (WKY) rats produced hypotension and bradycardia that were eliminated by prior injection into the NTS of the selective 5HT(2) antagonist sarpogrelate. Bilateral injection of sarpogrelate did not alter blood pressure or reflex changes in heart rate in response to phenylephrine-induced increases in blood pressure or nitroprusside-induced decreases in blood pressure. In SHR rats, the depressor response produced by injection of serotonin into the NTS was markedly larger than in WKY rats, and was larger than depressor responses previously reported for other excitatory substances injected into the NTS. In SHR rats bilateral injection of sarpogrelate produced an increase in blood pressure, although it did not alter baroreceptor-evoked changes in heart rate. These results provide further support for the hypothesis that stimulation of 5HT(2) receptors in the NTS contributes to cardiovascular regulation independent of the baroreceptor reflex. Furthermore, this serotonergic system is altered in SHR rats, apparently acting tonically to reduce blood pressure.

Electrophysiological evidence for reciprocal insulo-insular connectivity of baroreceptor-related neurons.

The recent indications of specialized lateralization of cardiovascular regulation within the right and left posterior insular cortex of the rat, suggest the possibility of transcallosal connectivity between these regions. This has not been previously demonstrated using physiological techniques. Extracellular neural recordings in 34 urethane anesthetized male Sprague-Dawley rats demonstrated reciprocal interinsular antidromic and orthodromic activation, elicited with similar median onset latencies (18 ms). The corresponding conduction velocity of these fibers (0.6 m/s) suggests that they may be unmyelinated. Many of the cells showing interhemispheric connectivity also responded to baroreceptor activation, further emphasizing the connectivity pattern in baroreceptor-related units. Both 1 and 25 Hz microstimulation of the contralateral insula indicated that the most frequent orthodromic response was inhibitory, either alone or as part of a biphasic pattern including activation. Chemical stimulation of the insula using L-glutamate was associated with both excitatory and inhibitory orthodromic activation of the contralateral posterior insula, confirming that the orthodromic electrical stimulation was not solely due to activation of fibers of passage. These data suggest that the two insulae may communicate with each other to integrate and balance cardiovascular function between hemispheres.

Anatomical substrates for baroreflex sympathoinhibition in the rat.

The fundamental neuronal substrates of the arterial baroreceptor reflex have been elucidated by combining anatomical, neurophysiological, and pharmacological approaches. A serial pathway between neurons located in the nuclei of the solitary tract (NTS), the caudal ventrolateral medulla (CVL), and the rostral ventrolateral medulla (RVL) plays a critical role in inhibition of sympathetic outflow following stimulation of baroreceptor afferents. In this paper, we summarize our studies using tract-tracing and electron microscopic immunocytochemistry to define the potential functional sites for synaptic transmission within this circuitry. The results are discussed as they relate to the literature showing: (1) baroreceptor afferents excite second-order neurons in NTS through the release of glutamate; (2) these NTS neurons in turn send excitatory projections to neurons in the CVL; (3) GABAergic CVL neurons directly inhibit RVL sympathoexcitatory neurons; and (4) activation of this NTS-->CVL-->RVL pathway leads to disfacilitation of sympathetic preganglionic neurons by promoting withdrawal of their tonic excitatory drive, which largely arises from neurons in the RVL. Baroreceptor control may also be regulated over direct reticulospinal pathways exemplified by a newly recognized sympathoinhibitory region of the medulla, the gigantocellular depressor area. This important autonomic reflex may also be influenced by parallel, multiple, and redundant networks.

Angiotensin peptides and baroreflex control of sympathetic outflow: pathways and mechanisms of the medulla oblongata.

The baroreceptor reflex is a relatively high gain control system that maintains arterial pressure within normal limits. To a large extent, this is accomplished through central neural pathways responsible for autonomic outflow residing in the medulla oblongata. The circulating renin-angiotensin system also contributes to the regulation of blood pressure, predominantly through its effects on the control of hydromineral balance and fluid volume. All the components of the renin-angiotensin system are also found in the brain. One of the principal products of the renin-angiotensin system cascade (brain or blood), angiotensin II, modulates the baroreceptor reflex by diminishing the sensitivity of the reflex and shifting the operating point for regulation of sympathetic outflow to higher blood pressures. This paper reviews our current knowledge about the neuronal pathways in the medulla oblongata through which angiotensin peptides alter the baroreceptor reflex control of sympathetic nerve activity. Emphasis is placed on the probable components and neural mechanisms of the medullary baroreflex arc that account for the ability of angiotensin peptides to change the sensitivity of the baroreceptor reflex and to shift the baroreceptor reflex control of sympathetic outflow to higher blood pressures in a pressure-independent manner.

Baroreflex dependent and independent roles of the caudal ventrolateral medulla in cardiovascular regulation.

The caudal ventrolateral medulla (CVLM) plays a critical role in cardiovascular regulation. Convincing data now support the hypothesis that inhibition of sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) by CVLM neurons constitutes the necessary inhibitory link in baroreceptor reflex mediated control of sympathetic vasomotor outflow. Inhibition or destruction of the CVLM produces severe acute hypertension, consistent with blockade of baroreceptor reflexes and withdrawal of inhibition of RVLM sympathoexcitatory neurons. However, other data indicate that the CVLM also tonically inhibits RVLM sympathoexcitatory neurons in a manner not driven by baroreceptor input. In some studies, inhibition of the CVLM results in an increase in arterial pressure (AP) without inhibiting baroreceptor reflexes, possibly reflecting baroreceptor-independent and baroreceptor-dependent sub-regions of the CVLM. Furthermore, in baroreceptor-denervated rats, inhibition of the CVLM still leads to large increases in AP. In addition, in spontaneously hypertensive rats (SHR) central processing of baroreceptor reflexes appears normal but CVLM-mediated inhibition of the RVLM seems to be attenuated, suggesting that it is specifically a baroreceptor-independent mechanism of cardiovascular regulation in SHR that is altered. Taken together, these findings support an important, tonic, baroreceptor-independent inhibition of RVLM sympathoexcitatory neurons exerted by the CVLM.