Somatosympathetic Reflex Research Articles

Maintenance of contractile force of the hind limb muscles by the somato-lumbar sympathetic reflexes

This study aimed to clarify whether the reflex excitation of muscle sympathetic nerves induced by contractions of the skeletal muscles modulates their contractility. In anesthetized rats, isometric tetanic contractions of the triceps surae muscles were induced by electrical stimulation of the intact tibial nerve before and after transection of the lumbar sympathetic trunk (LST), spinal cord, or dorsal roots. The amplitude of the tetanic force (TF) was reduced by approximately 10% at 20 min after transection of the LST, spinal cord, or dorsal roots. The recorded postganglionic sympathetic nerve activity from the lumbar gray ramus revealed that both spinal and supraspinal reflexes were induced in response to the contractions. Repetitive electrical stimulation of the cut peripheral end of the LST increased the TF amplitude. Our results indicated that the spinal and supraspinal somato-sympathetic nerve reflexes induced by contractions of the skeletal muscles contribute to the maintenance of their own contractile force.

Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3mgkg-1 per dose) 3 times a week for 14days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

Asymmetrical responses of skin blood flow in ischemic hindlimbs to electrical stimulation of the unilateral forelimb

The regulation of skin blood flow (SBF) is primarily mediated by the sympathetic nervous system, but the effects of electrical stimulation (ES) of one limb on SBF in the other limbs remain unknown. The present study investigated the effects of unilateral forelimb ES on SBF in the bilateral hindlimbs in anesthetized rats. Bilateral hindlimb ischemia was induced by tourniquet application for 60min. After reperfusion for 24h, ES (3 or 125Hz) was applied to the upper one-fourth of the triceps brachii muscle of the left or right forelimb for 30min. Rats that did not receive ES were used as the controls. Bilateral hindlimb SBF was measured by a laser Doppler line scanner for 20min before ES, 30min during ES, and 9min after ES. The results showed significant differences in SBF in the right but not left hindlimb between the control group and experimental group that received 125-Hz ES of the right forelimb. Right hindlimb SBF significantly increased within 3min following the application of 125-Hz ES to the right forelimb. No significant changes in SBF were observed in the left or right hindlimb when 125-Hz ES was applied to the left forelimb. Moreover, 3-Hz ES of the left or right forelimb did not significantly change SBF in either hindlimb compared with the control group. These results indicate that unilateral forelimb ES causes a differential SBF response in the hindlimb via a specific somatosympathetic reflex, and ES-induced SBF improvements in the ischemic hindlimb are frequency-dependent.

Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception.

The difficulty of defining the three so-called components of « an-esthesia » is emphasized: hypnosis, absence of movement, and adequacy of anti-nociception (intraoperative«analgesia »). Data obtained from anesthetized animals or humans delineate the activation of cardiac and vasomotor sympathetic reflex (somato-sympathetic reflex) and the cardiac parasympathetic deactivation observed following somatic stimuli. Sympathetic activation and parasympathetic deactivation are used as monitors to address the adequacy of intraoperative anti-nociception. Finally, intraoperative nociception through the administration of nonopioid analgesics vs. opioid analgesics is considered to achieve minimal postoperative side effects.

Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain

Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p’s<0.05) and T10 (p’s<0.05), but less so at T10 compared with T2 (p’s<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system.

Tonically Active cAMP-Dependent Signaling in the Ventrolateral Medulla Regulates Sympathetic and Cardiac Vagal Outflows.

The ventrolateral medulla contains presympathetic and vagal preganglionic neurons that control vasomotor and cardiac vagal tone, respectively. G protein-coupled receptors influence the activity of these neurons. Gα s activates adenylyl cyclases, which drive cyclic adenosine monophosphate (cAMP)-dependent targets: protein kinase A (PKA), the exchange protein activated by cAMP (EPAC), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. The aim was to determine the cardiovascular effects of activating and inhibiting these targets at presympathetic and cardiac vagal preganglionic neurons. Urethane-anesthetized rats were instrumented to measure splanchnic sympathetic nerve activity (sSNA), arterial pressure (AP), heart rate (HR), as well as baroreceptor and somatosympathetic reflex function, or were spinally transected and instrumented to measure HR, AP, and cardiac baroreflex function. All drugs were injected bilaterally. In the rostral ventrolateral medulla (RVLM), Sp-cAMPs and 8-Br-cAMP, which activate PKA, as well as 8-pCPT, which activates EPAC, increased sSNA, AP, and HR. Sp-cAMPs also facilitated the reflexes tested. Sp-cAMPs also increased cardiac vagal drive and facilitated cardiac baroreflex sensitivity. Blockade of PKA, using Rp-cAMPs or H-89 in the RVLM, increased sSNA, AP, and HR and increased HR when cardiac vagal preganglionic neurons were targeted. Brefeldin A, which inhibits EPAC, and ZD7288, which inhibits HCN channels, each alone had no effect. Cumulative, sequential blockade of all three inhibitors resulted in sympathoinhibition. The major findings indicate that Gα s-linked receptors in the ventral medulla can be recruited to drive both sympathetic and parasympathetic outflows and that tonically active PKA-dependent signaling contributes to the maintenance of both sympathetic vasomotor and cardiac vagal tone.

The influence of cervical spinal cord compression and vertebral displacement on somatosympathetic reflexes in the rat

Background contextOne theory within chiropractic proposes that vertebral subluxation in the upper cervical region induces spinal cord compression sufficient to alter spinal cord efferent output. We report on the feasibility of three different experimental approaches to test this theory. MethodsA high threshold electrical-evoked somatosympathetic reflex was recorded in adrenal or renal nerves of 10 anaesthetized adult male rats before and after (1) graded pressure was applied directly to the C1/C2 spinal cord segment in eight rats by the use of either direct compression or inflation of an extradural balloon and (2) displacement, less than a dislocation applied posterior to anterior, to the C2 vertebra in two rats. The latency and amplitude of the pre- and postintervention reflex responses were compared. ResultsThe reflex amplitude was not significantly changed by pressure (26 mmHg) from an extra-dural balloon or direct compression of the dura mater onto the dorsal spinal cord. Additional pressure, at least sufficient to occlude the dorsal vessels, induced a significant reduction in the amplitude of the reflex, and this reduction persisted for 20 minutes after removal of the pressure (Dunn's method for all pairwise multiple comparison Q stat=3.437; critical value for k=6 with α=0.05 is 2.936). Maximal vertebral (C2) displacement (4 mm), without dislocation did not induce significant changes compared with the control period. ConclusionsAlthough this feasibility study suggests it is unlikely that upper cervical vertebral subluxation, displacement less than a dislocation, compromises the sympathetic outflow in the adrenal or renal nerves, further vertebral displacement studies are necessary to formally test this.

Neuromedin U causes biphasic cardiovascular effects and impairs baroreflex function in rostral ventrolateral medulla of spontaneously hypertensive rat

Neuromedin U (NMU) causes biphasic cardiovascular and sympathetic responses and attenuates adaptive reflexes in the rostral ventrolateral medulla (RVLM) and spinal cord in normotensive animal. However, the role of NMU in the pathogenesis of hypertension is unknown. The effect of NMU on baseline cardiorespiratory variables in the RVLM and spinal cord were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male spontaneously hypertensive rats (SHR) and Wistar–Kyoto rats (WKY). Experiments were also conducted to determine the effects of NMU on somatosympathetic and baroreceptor reflexes in the RVLM of SHR and WKY. NMU injected into the RVLM and spinal cord elicited biphasic response, a brief pressor and sympathoexcitatory response followed by a prolonged depressor and sympathoinhibitory response in both hypertensive and normotensive rat models. The pressor, sympathoexcitatory and sympathoinhibitory responses evoked by NMU were exaggerated in SHR. Phrenic nerve amplitude was also increased following intrathecal or microinjection of NMU into the RVLM of both strains. NMU injection into the RVLM attenuated the somatosympathetic reflex in both SHR and WKY. Baroreflex sensitivity was impaired in SHR at baseline and further impaired following NMU injection into the RVLM. NMU did not affect baroreflex activity in WKY. The present study provides functional evidence that NMU can have an important effect on the cardiovascular and reflex responses that are integrated in the RVLM and spinal cord. A role for NMU in the development and maintenance of essential hypertension remains to be determined.

The Somatosympathetic Reflex in Rats with Different Models of Arterial Hypertension

The aim of the present work was to perform a comparative study of the magnitudes of spontaneous and evoked (by single afferent stimuli) activity in a sympathetic nerve in animals with arterial hypertension of different causes. Acute experiments on anesthetized Wistar rats with renovascular hypertension and rats of the spontaneously hypertensive strain SHR were performed to record spontaneous and evoked (somatosympathetic reflex) activity in the cervical sympathetic trunk. Tonic electrical activity in the sympathetic nerve in hypertensive rats was greater than that in normotensive individuals. The magnitudes of the somatosympathetic reflex in rats with models of arterial hypertension differed from that of the reflex in control animals. The magnitude of the reflex was decreased in rats with the renovascular model of hypertension, while the reflex was increased in rats with spontaneous hypertension, as compared with normotensive animals. The time characteristics of the reflex in hypertensive rats also showed differences. It is suggested that different components of the brainstem show different changes in their functional activity in rats with different experimental models of hypertension.

Intrathecal melanin-concentrating hormone reduces sympathetic tone and blocks cardiovascular reflexes

Melanin-concentrating hormone (MCH) is a neuropeptide that acts to increase feeding behavior and decrease energy expenditure. The role of MCH in central cardiorespiratory regulation is still poorly understood. Experiments were conducted on urethane-anesthetized, vagotomized, and artificially ventilated male Sprague-Dawley rats (n = 22) to ascertain whether MCH modulates sympathetic vasomotor tone, as well as barosympathetic, chemosympathetic, and somatosympathetic reflexes at the level of the spinal cord. Intrathecal injection of 10 μl of MCH produced a dose-dependent hypotension, bradycardia, and sympathoinhibition. Peak response was observed following administration of 1 mM MCH, causing a decrease in mean arterial pressure of 39 ± 2 mmHg (P < 0.001), splanchnic sympathetic nerve activity of 78 ± 11% (P < 0.001), and heart rate of 87 ± 11 beats per minute (bpm) (P < 0.01). The two peaks of the somatosympathetic reflex were decreased by intrathecal MCH, 7 ± 3% (P < 0.01) and 31 ± 6% (P < 0.01), respectively, and the spinal component of the reflex was accentuated 96 ± 23% (P < 0.05), with respect to the baseline for MCH, compared with the two peaks and spinal component of the somatosympathetic reflex elicited following saline injection with respect to the baseline for saline. MCH decreased the sympathetic gain to 120 s of hyperoxic hypercapnea (10% CO(2) in 90% O(2)) and to 10-12 s poikilocapneic anoxia (100% N(2)) from 0.74 ± 0.14%/s to 0.23 ± 0.04%/s (P < 0.05) and 16.47 ± 3.2% to 4.35 ± 1.56% (P < 0.05), respectively. There was a 34% decrease in gain and a 62% decrease in range of the sympathetic baroreflex with intrathecal MCH. These data demonstrate that spinal MCH blunts the central regulation of sympathetic tone and adaptive sympathetic reflexes.

Orexin A in rat rostral ventrolateral medulla is pressor, sympatho‐excitatory, increases barosensitivity and attenuates the somato‐sympathetic reflex

The rostral ventrolateral medulla (RVLM) maintains sympathetic nerve activity (SNA), and integrates adaptive reflexes. Orexin A-immunoreactive neurones in the lateral hypothalamus project to the RVLM. Microinjection of orexin A into RVLM increases blood pressure and heart rate. However, the expression of orexin receptors, and effects of orexin A in the RVLM on splanchnic SNA (sSNA), respiration and adaptive reflexes are unknown. The effect of orexin A on baseline cardio-respiratory variables as well as the somato-sympathetic, baroreceptor and chemoreceptor reflexes in RVLM were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats (n= 50). orexin A and its receptors were detected with fluorescence immunohistochemistry. Tyrosine hydroxylase-immunoreactive neurones in the RVLM were frequently co-localized with orexin 1 (OX(1) ) and orexin 2 (OX(2) ) receptors and closely apposed to orexin A-immunoreactive terminals. Orexin A injected into the RVLM was pressor and sympatho-excitatory. Peak effects were observed at 50 pmol with increased mean arterial pressure (42 mmHg) and SNA (45%). Responses to orexin A (50 pmol) were attenuated by the OX(1) receptor antagonist, SB334867, and reproduced by the OX(2) receptor agonist, [Ala(11) , D-Leu(15) ]orexin B. Orexin A attenuated the somato-sympathetic reflex but increased baroreflex sensitivity. Orexin A increased or reduced sympatho-excitation following hypoxia or hypercapnia respectively. Although central cardio-respiratory control mechanisms at rest do not rely on orexin, responses to adaptive stimuli are dramatically affected by the functional state of orexin receptors.

Differential Cardiorespiratory and Sympathetic Reflex Responses to Microinjection of Neuromedin U in Rat Rostral Ventrolateral Medulla

The rostral ventrolateral medulla (RVLM) regulates sympathetic vasomotor outflow and reflexes. Intracerebroventricular neuromedin U (NMU) increases sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR), but the central nuclei that mediate these effects are unknown. In urethane-anesthetized, vagotomized, and artificially ventilated male Sprague-Dawley rats (n = 36) the effects of bilateral microinjection of NMU (50 nl, each side) into RVLM on cardiorespiratory variables, somatosympathetic reflex, arterial baroreflex, and chemoreflex were investigated. Microinjection of NMU into RVLM elicited a hypertension, tachycardia, and an increase in splanchnic SNA (SSNA) and lumbar SNA (LSNA) at lower doses (25 and 50 pmol). At higher dose (100 pmol), NMU caused a biphasic response, a brief hypertension and sympathoexcitation followed by prolonged hypotension and sympathoinhibition. The peak excitatory and inhibitory response was found at 100 pmol NMU with an increase in MAP, HR, SSNA, and LSNA of 36 mm Hg, 20 beats per minute, 34%, and 89%, respectively, and a decrease of 33 mm Hg, 25 beats per minute, 42%, and 52%, respectively, from baseline. NMU, in the RVLM, also increased phrenic nerve amplitude and the expiratory period and reduced the inspiratory period. NMU (100 pmol) attenuated the somatosympathetic reflex and the sympathoexcitatory and respiratory responses to hypoxia and hypercapnia. After NMU injection in RVLM, the maximum gain of the SSNA baroreflex function curve was increased, but that of the LSNA was reduced. The present study provides functional evidence for a complex differential modulatory activity of NMU on the cardiovascular and reflex responses that are integrated in the RVLM.

Somatosympathetic Vasoconstrictor Reflexes in Human Spinal Cord Injury: Responses to Innocuous and Noxious Sensory Stimulation below Lesion

It is known that the sudden increases in blood pressure associated with autonomic dysreflexia in people with spinal cord injury (SCI) are due to a spinally mediated reflex activation of sympathetic vasoconstrictor neurons supplying skeletal muscle and the gut. Apart from visceral inputs, such as those originating from a distended bladder, there is a prevailing opinion that autonomic dysreflexia can be triggered by noxious stimulation below the lesion. However, do noxious inputs really cause an increase in blood pressure in SCI? Using microelectrodes inserted into a peripheral nerve to record sympathetic nerve activity we had previously shown that selective stimulation of small-diameter afferents in muscle or skin, induced by bolus injection of hypertonic saline into the tibialis anterior muscle or the overlying skin, evokes a sustained increase in muscle sympathetic nerve activity and blood pressure and a transient increase in skin sympathetic nerve activity and decrease in skin blood flow in able-bodied subjects. We postulated that these sympathetic responses would be exaggerated in SCI, with a purely noxious stimulus causing long-lasting increases in blood pressure and long-lasting decreases in skin blood flow. Surprisingly, though, we found that intramuscular or subcutaneous injection of hypertonic saline into the leg caused negligible changes in these parameters. Conversely, weak electrical stimulation over the abdominal wall, which in able-bodied subjects is not painful and activates large-diameter cutaneous afferents, caused a marked increase in blood pressure in SCI but not in able-bodied subjects. This suggests that it is activation of large-diameter somatic afferents, not small-diameter afferents, that triggers increases in sympathetic outflow in SCI. Whether the responses to activation of large-diameter afferents reflect plastic changes in the spinal cord in SCI is unknown.

Prominent contribution of L-type Ca2+channels to cutaneous neurovascular transmission that is revealed after spinal cord injury augments vasoconstriction

In patients with spinal cord injury (SCI), somatosympathetic reflexes produce exaggerated decreases in skin blood flow below the lesion. This hypoperfusion appears to result from an increased responsiveness of cutaneous arterial vessels to neural activation. Here we investigated the mechanisms that underlie SCI-induced enhancement of neurovascular transmission in a cutaneous vessel, the rat tail artery. Isometric contractions of arterial segments from T11 spinal cord transected and sham-operated rats were compared 6 wk postoperatively. SCI more than doubled the amplitudes of contractions of arteries in response to moderate frequencies of nerve stimulation (0.1 to 1 Hz). In arteries from SCI rats, but not those from sham-operated rats, the L-type Ca(2+) channel blocker nifedipine (1 μM) reduced the amplitudes of nerve-evoked contractions. Furthermore, while the sensitivity to the agonists phenylephrine (α(1)-adrenoceptor selective) and clonidine (α(2)-adrenoceptor selective) did not differ significantly between arteries from SCI and sham-operated rats, nifedipine had a greater inhibitory effect on contractions to both agents in arteries from SCI rats. Although sensitivity to clonidine was unchanged, SCI selectively reduced the contribution of postjunctional α(2)-adenceptors to nerve-evoked contractions. In arteries from unoperated rats, the L-type channel agonist BAY K 8644 (0.1 μM) produced a similar enhancement of nerve-evoked contraction to that produced by SCI and also selectively reduced the contribution of α(2)-adrenceptors to these responses. Together the findings demonstrate that the SCI-induced enhancement of neurovascular transmission in the rat tail artery can largely be accounted for by an increased contribution of L-type Ca(2+) channels to activation of the vascular smooth muscle.

Intrathecal neuromedin U induces biphasic effects on sympathetic vasomotor tone, increases respiratory drive and attenuates sympathetic reflexes in rat

Neuromedin U (NMU) is a brain-gut peptide that plays regulatory roles in feeding, anxiety, smooth muscle contraction, blood flow, pain and adrenocortical function via two receptors, the NMU receptor 1 and NMU receptor 2. NMU has several known functions in the periphery, but its role in central cardiorespiratory regulation remains poorly understood. Experiments were conducted on urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats (n= 42) to determine if NMU modulates sympathetic vasomotor output at the spinal level or modulates baro-, chemo- and somato-sympathetic reflexes. Intrathecal (i.t.) injections of NMU (2.5-20 nmol) caused a dose-dependent biphasic response, initially a brief period of hypertension and sympatho-excitation followed by prolonged hypotension and sympatho-inhibition. Peak excitatory as well as inhibitory responses were observed at 20 nmol. NMU (20 nmol) initially increased mean arterial pressure and splanchnic sympathetic nerve activity by 24 mmHg and 27% and then reduced these by 37 mmHg and 47%, respectively. NMU also dose-dependently increased respiratory drive, as indicated by a rise in phrenic nerve amplitude, an increase in neural minute ventilation and a shortening of the inspiratory period. Both sympatho-excitatory peaks of the somato-sympathetic reflex were abolished by i.t. NMU. Pressor, sympatho-excitatory and tachycardiac responses to chemoreceptor activation (100% N₂) were blocked or significantly reduced following i.t. NMU. NMU also reduced barosensitivity. The data demonstrate that NMU, acting in the spinal cord, differentially contributes to the control of sympathetic tone and adaptive sympathetic reflexes.

Patterning of somatosympathetic reflexes reveals nonuniform organization of presympathetic drive from C1 and non-C1 RVLM neurons

To determine the organization of presympathetic vasomotor drive by phenotypic populations of rostral ventrolateral medulla (RVLM) neurons, we examined the somatosympathetic reflex (SSR) evoked in four sympathetic nerves together with selective lesions of RVLM presympathetic neurons. Urethane-anesthetized (1.3 g/kg ip), paralyzed, vagotomized and artificially ventilated Sprague-Dawley rats (n = 41) were used. First, we determined the afferent inputs activated by sciatic nerve (SN) stimulation at graded stimulus intensities (50 sweeps at 0.5-1 Hz, 1-80 V). Second, we recorded sympathetic nerve responses (cervical, renal, splanchnic, and lumbar) to intensities of SN stimulation that activated A-fiber afferents (low) or both A- and C-fiber afferents (high). Third, with low-intensity SN stimulation, we examined the cervical SSR following RVLM microinjection of somatostatin, and we determined the splanchnic SSR in rats in which presympathetic C1 neurons were lesioned following intraspinal injections of anti-dopamine-β-hydroxylase-saporin (anti-DβH-SAP). Low-intensity SN stimulation activated A-fiber afferents and evoked biphasic responses in the renal, splanchnic, and lumbar nerves and a single peak in the cervical nerve. Depletion of presympathetic C1 neurons (59 ± 4% tyrosine hydroxylase immunoreactivity profiles lesioned) eliminated peak 2 of the splanchnic SSR and attenuated peak 1, suggesting that only RVLM neurons with fast axonal conduction were spared. RVLM injections of somatostatin abolished the single early peak of cervical SSR confirming that RVLM neurons with fast axonal conduction were inhibited by somatostatin. It is concluded that unmyelinated RVLM presympathetic neurons, presumed to be all C1, innervate splanchnic, renal, and lumbar but not cervical sympathetic outflows, whereas myelinated C1 and non-C1 RVLM neurons innervate all sympathetic outflows examined. These findings suggest that multiple levels of neural control of vasomotor tone exist; myelinated populations may set baseline tone, while unmyelinated neurons may be recruited to provide actions at specific vascular beds in response to distinct stressors.

Intrathecal orexin A increases sympathetic outflow and respiratory drive, enhances baroreflex sensitivity and blocks the somato‐sympathetic reflex

Intrathecal (i.t.) injection of orexin A (OX-A) increases blood pressure and heart rate (HR), but the effects of OX-A on sympathetic and phrenic, nerve activity, and the baroreflex(es), somato-sympathetic and hypoxic chemoreflex(es) are unknown. Urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats were examined in this study. The effects of i.t. OX-A (20 nmol 10 µL⁻¹) on cardiorespiratory parameters, and responses to stimulation of the sciatic nerve (electrical), arterial baroreceptors (phenylephrine hydrochloride, 0.01 mg kg⁻¹ i.v.) and peripheral (hypoxia) chemoreceptors were also investigated. i.t. OX-A caused a prolonged dose-dependent sympathoexcitation, pressor response and tachycardia. The peak effect was observed at 20 nmol with increases in mean arterial pressure, HR and splanchnic sympathetic nerve activity (sSNA) of 32 mmHg, 52 beats per minute and 100% from baseline respectively. OX-A also dose-dependently increased respiratory drive, as indicated by a rise in phrenic nerve amplitude and a fall in phrenic nerve frequency, an increase in neural minute ventilation, a lengthening of the expiratory period, and a shortening of the inspiratory period. All effects of OX-A (20 nmol) were attenuated by the orexin receptor 1 antagonist SB 334867. OX-A significantly reduced both sympathoexcitatory peaks of somato-sympathetic reflex while increasing baroreflex sensitivity. OX-A increased the amplitude of the pressor response and markedly amplified the effect of hypoxia on sSNA. Thus, activation of OX receptors in rat spinal cord alters cardiorespiratory function and differentially modulates sympathetic reflexes.

Tuning the gain of somato-sympathetic reflexes by stimulation of the thoracic spine in humans

In animals, somatic stimulation of the limbs can evoke sympathetic reflexes of supraspinal origin. In addition, spinal reflexes can be elicited by stimulation of somatic tissues of the trunk. However, limited evidence is available concerning the specific modulation of sympathetic reflexes by afferents from the thoracic spine. This has also been largely overlooked in healthy humans. The aim of the present study was to determine whether tonic noxious heat (NH) applied to the skin over T3–T5 could segmentally increase supraspinal sympathetic reflexes (skin conductance responses – SCRs) induced by phasic electrical stimulation of the sural nerve. In addition, the effect of spinal manipulation (SM) on SCR amplitude and SCR amplification by NH was investigated. During the control session, palmar and plantar SCR amplitude was stable, showing no significant modulation. During NH and SM, however, palmar SCR amplitude was respectively increased and decreased in comparison to baseline, leading to a robust difference in SCR amplitude between the 2 conditions ( p < 0.001). Moreover, these changes were also significantly and marginally different compared to the control session ( p = 0.041 and p = 0.053, respectively). Interestingly, when applied immediately before NH, SM had a preventive effect on palmar SCR amplification induced by NH. In sharp contrast, changes in plantar SCRs were not significantly different between sessions ( p = 0.42). Altogether, these results indicate that somatic stimulation of the thoracic spine may modulate somato-sympathetic reflexes segmentally in conscious, healthy volunteers.

Tonic and reflex control of the cardio-respiratory system by neurons in the ventral medulla

To investigate the channels and neurotransmitters in the ventrolateral medulla (VLM) oblongata that are responsible for the maintenance of sympathetic tone and cardio-respiratory reflex regulation. Microinjections of excitant amino acid (glutamate, 100 nl, 100 mM), calcium channel blockers, agonists and antagonists were made throughout the VLM in anaesthetized rats. Arterial blood pressure, sympathetic nerve activity and phrenic nerve discharge was recorded. Responses to activation of the baroreceptor, somatosympathetic, and chemoreceptor reflexes were recorded. Injection sites were marked with albumin-colloidal gold or methylene blue. At the end of recording, brains were removed, fixed, sectioned and stained for gold spots, and counterstained to localize injection sites. Bilateral microinjection of calcium channel antagonists into the rostral VLM (RVLM) had little effect on arterial blood pressure with the exception of Ni++ (an agent that blocks low voltage T-type calcium channels). Ni++ caused a profound fall in arterial blood pressure and sympathetic nerve activity, but did not affect reflex function. By contrast the high voltage channel (P, Q, L, N) blockers increased blood pressure and sympathetic activity following injection into the caudal VLM (CVLM). The agents applied were 8-OHDPAT; 5HT1a agonist, DAMGO; mu opioid agonist, DPDPE; delta opioid agonist and sar9-substance P; substance P agonist. In addition, the effect of changing the inhaled concentration of carbon dioxide was tested. In all cases except injection DAMGO, there was an attenuation of the somato-sympathetic reflex. DAMGO attenuated the baroreceptor reflex. None of these agents affected the chemoreceptor reflex. The data suggest that tonic maintenance of sympathetic activity is mediated, at least in part, by a Ni++ sensitive conductance in RVLM and that the neurochemical heterogeneity found within the inputs to sympathoexcitatory and inhibitory neurons in the RVLM has functional significance, with different neurotransmitters affecting cardiorespiratory reflexes differentially. Further functional studies are required to determine the precise connectivity between different neuronal populations that are subserving different functions in the RVLM.

Catestatin in rat RVLM is sympathoexcitatory, increases barosensitivity, and attenuates chemosensitivity and the somatosympathetic reflex

The fundamental role and corollary effects of neuropeptides that govern cardiorespiratory control in the brain stem are poorly understood. One such regulatory peptide, catestatin [Cts, human chromogranin A-(352-372)], noncompetitively inhibits nicotinic-cholinergic-stimulated catecholamine release. Previously, we demonstrated the presence of chromogranin A mRNA in brain stem neurons that are important for the maintenance of arterial pressure. In the present study, using immunofluorescence histochemistry, we show that Cts immunoreactivity is colocalized with tyrosine hydroxylase in C1 neurons of the rostral ventrolateral medulla (RVLM, n = 3). Furthermore, we investigated the effects of Cts on resting blood pressure, splanchnic sympathetic nerve activity, phrenic nerve activity, heart rate, and adaptive reflexes. Cts (1 mM in 50 nl or 100 μM in 50-100 nl) was microinjected into the RVLM in urethane-anesthetized, vagotomized, ventilated Sprague-Dawley rats (n = 19). Cardiovascular responses to stimulation of carotid baroreceptors, peripheral chemoreceptors, and the sciatic nerve (somatosympathetic reflex) were analyzed. Cts (1 mM in 50 nl) increased resting arterial pressure (28 ± 3 mmHg at 2 min postinjection), sympathetic nerve activity (15 ± 3% at 2 min postinjection), and phrenic discharge amplitude (31 ± 4% at 10 min postinjection). Cts increased sympathetic barosensitivity 40% (slope increased from -0.05 ± 0.01 before Cts to -0.07 ± 0.01 after Cts) and attenuated the somatosympathetic reflex [1st peak: 36% (from 132 ± 32.1 to 84.0 ± 17.0 μV); 2nd peak: 44% (from 65.1 ± 21.4 to 36.6 ± 14.1 μV)] and chemoreflex (blood pressure response to anoxia decreased 55%, sympathetic response decreased 46%). The results suggest that Cts activates sympathoexcitatory bulbospinal neurons in the RVLM and plays an important regulatory role in adaptive reflexes.