NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

2005 ◽  
Vol 288 (6) ◽  
pp. R1707-R1715 ◽  
Author(s):  
John M. Makeham ◽  
Ann K. Goodchild ◽  
Paul M. Pilowsky
Keyword(s):  
Substance P ◽  
Phrenic Nerve ◽  
Receptor Activation ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Nk1 Receptor ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Phrenic Nerve Activity ◽  
Arterial Blood

The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the rostral ventrolateral medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, the somato-sympathetic reflex, baroreflex, and chemoreflex were studied in urethane-anesthetized and artificially ventilated Sprague-Dawley rats. Bilateral microinjection of either the stable substance P analog (pGlu5, MePhe8, Sar9)SP(5–11) (DiMe-SP) or the highly selective NK1 agonist [Sar9, Met (O2)11]SP into the RVLM resulted in an increase in ABP, sSNA, and heart rate and an abolition of phrenic nerve activity. The effects of [Sar9, Met (O2)11]SP were blocked by the selective nonpeptide NK1 receptor antagonist WIN 51708. NK1 receptor activation also dramatically attenuated the somato-sympathetic reflex elicited by tibial nerve stimulation, while leaving the baroreflex and chemoreflex unaffected. This effect was again blocked by WIN 51708. NK1 receptor antagonism in the RVLM, with WIN 51708 significantly attenuated the sympathoexcitatory response to hypoxia but had no effect on baseline respiratory function. Our findings suggest that substance P and the NK1 receptor play a significant role in the cardiorespiratory reflexes integrated within the RVLM.

scholarly journals Selected Contribution: Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia

2001 ◽  
Vol 90 (5) ◽  
pp. 2001-2006 ◽  
Author(s):  
D. D. Fuller ◽  
A. G. Zabka ◽  
T. L. Baker ◽  
G. S. Mitchell
Keyword(s):  
Receptor Antagonist ◽  
Phrenic Nerve ◽  
Receptor Activation ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Sprague Dawley Rats ◽  
Episodic Hypoxia ◽  
Baseline Levels ◽  
Long Term Facilitation

Episodic hypoxia evokes a sustained augmentation of respiratory motor output known as long-term facilitation (LTF). Phrenic LTF is prevented by pretreatment with the 5-hydroxytryptamine (5-HT) receptor antagonist ketanserin. We tested the hypothesis that 5-HT receptor activation is necessary for the induction but not maintenance of phrenic LTF. Peak integrated phrenic nerve activity (∫Phr) was monitored for 1 h after three 5-min episodes of isocapnic hypoxia (arterial Po 2 = 40 ± 2 Torr; 5-min hyperoxic intervals) in four groups of anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats [ 1) control ( n = 11), 2) ketanserin pretreatment (2 mg/kg iv; n = 7), and ketanserin treatment 0 and 45 min after episodic hypoxia ( n = 7 each)]. Ketanserin transiently decreased ∫Phr, but it returned to baseline levels within 10 min. One hour after episodic hypoxia, ∫Phr was significantly elevated from baseline in control and in the 0- and 45-min posthypoxia ketanserin groups. Conversely, ketanserin pretreatment abolished phrenic LTF. We conclude that 5-HT receptor activation is necessary to initiate (during hypoxia) but not maintain (following hypoxia) phrenic LTF.

Intrathecal bombesin is sympathoexcitatory and pressor in rat

2011 ◽  
Vol 301 (5) ◽  
pp. R1486-R1494 ◽  
Author(s):  
Branimir Zogovic ◽  
Paul M. Pilowsky
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Phrenic Nerve ◽  
Nerve Activity ◽  
Thoracic Spinal Cord ◽  
Phrenic Nerve Activity ◽  
Amino Acid Peptide ◽  
Arterial Blood ◽  
Thoracic Spinal

Bombesin, a 14 amino-acid peptide, is pressor when administered intravenously in rat and pressor and sympathoexcitatory when applied intracerebroventricularly. To determine the spinal effects of bombesin, the peptide was administered acutely in the intrathecal space at around thoracic spinal cord level six of urethane-anesthetized, paralyzed, and bilaterally vagotomized rats. Blood pressure, heart rate, splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, and end-tidal CO2 were monitored to evaluate changes in the cardiorespiratory systems. Bombesin elicited a long-lasting excitation of sSNA associated with an increase in blood pressure and tachycardia. There was a mean increase in arterial blood pressure of 52 ± 5 mmHg (300 μM; P < 0.01). Heart rate and sSNA also increased by 40 ± 4 beats/min ( P < 0.01) and 162 ± 33% ( P < 0.01), respectively. Phrenic nerve amplitude (PNamp, 73 ± 8%, P < 0.01) and phrenic expiratory period (+0.16 ± 0.02 s, P < 0.05) increased following 300 μM bombesin. The gain of the sympathetic baroreflex increased from −2.8 ± 0.7 to −5.4 ± 0.9% ( P < 0.01), whereas the sSNA range was increased by 99 ± 26% ( P < 0.01). During hyperoxic hypercapnia (10% CO2 in O2, 90 s), bombesin potentiated the responses in heart rate (−25 ± 5 beats/min, P < 0.01) and sSNA (+136 ± 29%, P < 0.001) but reduced PNamp (from 58 ± 6 to 39 ± 7%, P < 0.05). Finally, ICI-216,140 (1 mM), an in vivo antagonist for the bombesin receptor 2, attenuated the effects of 300 μM bombesin on blood pressure (21 ± 7 mmHg, P < 0.01). We conclude that bombesin is sympathoexcitatory at thoracic spinal segments. The effect on phrenic nerve activity may the result of spinobulbar pathways and activation of local motoneuronal pools.

scholarly journals Spinal NMDA receptor activation is necessary for de novo, but not the maintenance of, A2a receptor-mediated phrenic motor facilitation

2009 ◽  
Vol 107 (1) ◽  
pp. 217-223 ◽  
Author(s):  
F. J. Golder
Keyword(s):  
Nmda Receptor ◽  
Phrenic Nerve ◽  
De Novo ◽  
Receptor Activation ◽  
Nerve Activity ◽  
Mk 801 ◽  
Phrenic Nerve Activity ◽  
Cgs 21680 ◽  
A2a Receptor ◽  
Nmda Receptor Activation

Adenosine 2a (A2a) receptor agonists elicit persistent increases in phrenic nerve activity by transactivating the neurotrophin receptor, TrkB, near phrenic motoneurons. Our working model proposes that A2a receptor-mediated TrkB receptor activation strengthens glutamatergic synapses onto phrenic motoneurons. Activation of glutamate N-methyl d-aspartate (NMDA) receptors has been implicated in other models of phrenic motor plasticity. Thus we hypothesized that NMDA receptor activation also would contribute to A2a receptor-mediated phrenic motor facilitation. Adult male Sprague-Dawley rats were anesthetized with urethane, mechanically ventilated, neuromuscularly paralyzed, and bilaterally vagotomized. The A2a receptor agonist CGS-21680 and the NMDA receptor-channel blocker MK-801 were administered intrathecally over the C4 spinal segment. Phrenic nerve activity was recorded before, during, and after drug administration. MK-801 (concentration range 0.1, 1.0, 10.0, and 100 μM) was administered 30 min before CGS-21680 (50 μM). MK-801 dose-dependently blocked A2a receptor-mediated phrenic motor facilitation. When administered at 60 min post-CGS-21680, MK-801 prevented further increases in phrenic nerve activity compared with the CGS-21680 alone (CGS-21680 alone at 120 min: 114 ± 19%; CGS-21680 and MK-801 at 60 min post-CGS-21680: 61 ± 11%, above baseline, P < 0.05) but did not return phrenic motor output to baseline values. Our data suggest that NMDA receptor activation is necessary for de novo A2a receptor-mediated phrenic motor facilitation and that the maintenance of preexisting phrenic motor facilitation does not involve NMDA receptor-dependent mechanisms.

scholarly journals The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances

2009 ◽  
Vol 364 (1529) ◽  
pp. 2611-2623 ◽  
Author(s):  
M. Dutschmann ◽  
H. Waki ◽  
T. Manzke ◽  
A. E. Simms ◽  
A. E. Pickering ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Vascular Resistance ◽  
Phrenic Nerve ◽  
Sympathetic Activity ◽  
Nerve Activity ◽  
Cardiorespiratory Control ◽  
Conscious Rats ◽  
Phrenic Nerve Activity ◽  
Arterial Blood

Serotonin receptor (5-HTR) agonists that target 5-HT 4(a) R and 5-HT 1A R can reverse μ-opioid receptor (μ-OR)-evoked respiratory depression. Here, we have tested whether such rescuing by serotonin agonists also applies to the cardiovascular system. In working heart–brainstem preparations in situ , we have recorded phrenic nerve activity, thoracic sympathetic chain activity (SCA), vascular resistance and heart rate (HR) and in conscious rats, diaphragmatic electromyogram, arterial blood pressure (BP) and HR via radio-telemetry. In addition, the distribution of 5-HT 4(a) R and 5-HT 1A R in ponto-medullary cardiorespiratory networks was identified using histochemistry. Systemic administration of the μ-OR agonist fentanyl in situ decreased HR, vascular resistance, SCA and phrenic nerve activity. Subsequent application of the 5-HT 1A R agonist 8-OH-DPAT further enhanced bradycardia, but partially compensated the decrease in vascular resistance, sympathetic activity and restored breathing. By contrast, the 5-HT 4(a) R agonist RS67333 further decreased vascular resistance, HR and sympathetic activity, but partially rescued breathing. In conscious rats, administration of remifentanyl caused severe respiratory depression, a decrease in mean BP accompanied by pronounced bradyarrhythmia. 8-OH-DPAT restored breathing and prevented the bradyarrhythmia; however, BP and HR remained below baseline. In contrast, RS67333 further suppressed cardiovascular functions in vivo and only partially recovered breathing in some cases. The better recovery of μ-OR cardiorespiratory disturbance by 5-HT 1A R than 5-HT 4(a) R is supported by the finding that 5-HT 1A R was more densely expressed in key brainstem nuclei for cardiorespiratory control compared with 5-HT 4(a) R. We conclude that during treatment of severe pain, 5-HT 1A R agonists may provide a useful tool to counteract opioid-mediated cardiorespiratory disturbances.

Role of the ventral surface of medulla in the generation of Mayer waves

1989 ◽  
Vol 257 (4) ◽  
pp. R804-R809 ◽  
Author(s):  
M. A. Haxhiu ◽  
E. van Lunteren ◽  
E. C. Deal ◽  
N. S. Cherniack
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Phrenic Nerve ◽  
Pressure Oscillation ◽  
Nerve Activity ◽  
Intermediate Area ◽  
Mayer Waves ◽  
Phrenic Nerve Activity ◽  
Arterial Blood ◽  
Cyclic Changes

The regions adjacent to the ventrolateral medullary surface (VMS) play critical roles in the regulation of respiratory and cardiovascular function. Furthermore, these areas seem to be important sites for the integration of afferent inputs from certain sensory organs and the source of excitatory inputs to preganglionic sympathetic and parasympathetic neurons. To determine whether the VMS contributes to the generation of nonrespiratory-related periodic oscillations of arterial blood pressure (Mayer waves), excitatory substances, such as N-methyl-D-aspartate (NMDA), cholinergic agonists, and neuropeptides (substance P, neurokinin A, neurotensin), were applied topically to the intermediate area of VMS in anesthetized cats. In addition, the effects of application of lidocaine and inhibitory substances (benzodiazepines) on Mayer waves were studied. After application of excitatory substances to the VMS, we observed oscillations of arterial blood pressure, recurring with a period of 17.8 +/- 10 (SE) s, which had similar characteristics as the Mayer waves recorded during hypercapnia or hypoxia. In addition, cyclic changes in phrenic nerve activity and tracheal tone occurred with the same periodicity as arterial blood pressure oscillation. Application of lidocaine or benzodiazepines on the intermediate area of the VMS abolished Mayer waves observed during hypercapnia, hypoxia, or application of excitatory substances. These findings show for the first time that the VMS can be considered as one of several synaptic relays involved in the generation of arterial blood pressure oscillation, as well as the cyclic changes in phrenic nerve activity and tracheal smooth muscle tone that occur simultaneously.

Differential effects from parapyramidal region and rostral ventrolateral medulla mediated by substance P

1999 ◽  
Vol 277 (4) ◽  
pp. R1120-R1129
Author(s):  
Kenneth Swiatkowski ◽  
Lynn M. Dellamano ◽  
John Vissing ◽  
Kenneth J. Rybicki ◽  
Gerald P. Kozlowski ◽  
...  
Keyword(s):  
Substance P ◽  
Intrathecal Injection ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Cell Column ◽  
Arterial Blood ◽  
Pressor Responses ◽  
General Response ◽  
Subretrofacial Area ◽  
Anesthetized Cat

Rostral ventrolateral medulla (rVLM) and parapyramidal region (PPr) serve as important medullary control sites for sympathoexcitation. rVLM and PPr have direct projections to the intermediolateral cell column (IML) that are thought to be important in maintaining mean arterial blood pressure (MAP). Substance P (SP) is found in PPr neurons and in and near the subretrofacial area of the rVLM. At least some of these cells project to the IML. We investigated the involvement of SP at the IML in mediating rVLM- and PPr-evoked pressor responses in the chloralose-anesthetized cat. Pressor responses to electrical and chemical PPr and rVLM stimulation were altered after intrathecal injection, at the level of the T1-T3 spinal cord, of either SP antagonist [d-Pro2,d-Phe7,d-Trp9]-SP, SP antagonist CP 96,345, or SP antiserum. Although MAP and heart rate responses to PPr stimulation were attenuated by intrathecal SP antagonists or antiserum, MAP responses to rVLM stimulation were augmented. Previous studies have revealed differences in transmitters associated with these two areas, even though the general response of both areas is sympathoexcitatory. The present study implies that the identical substance may increase or decrease the MAP response depending on the pathway activated.

scholarly journals Activation of µ-opioid receptors in the rostral ventrolateral medulla blocks the sympathetic counterregulatory response to glucoprivation

2018 ◽  
Vol 315 (6) ◽  
pp. R1115-R1122 ◽  
Author(s):  
Zohra M. Kakall ◽  
Polina E. Nedoboy ◽  
Melissa M. J. Farnham ◽  
Paul M. Pilowsky
Keyword(s):  
Opioid Receptors ◽  
Glucose Production ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Efferent Nerve ◽  
Glucose Levels ◽  
Sprague Dawley Rats ◽  
Adrenaline Release

Activation of neurons in the rostral ventrolateral medulla (RVLM) following glucoprivation initiates sympathoadrenal activation, adrenaline release, and increased glucose production. Here, we aimed to determine the role of RVLM µ-opioid receptors in the counterregulatory response to systemic glucoprivation. Experiments were performed in pentobarbital sodium anesthetized male Sprague-Dawley rats ( n = 30). Bilateral activation of RVLM µ-opioid receptors with [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (8 mM, 50 nl) depressed adrenal sympathetic nerve activity for ~60 min ( n = 6; Δ49.9 ± 5.8%, P < 0.05). The counterregulatory response to glucoprivation (measured by adrenal sympathetic efferent nerve activity) induced by 2-deoxyglucose (2-DG) ( n = 6; Δ63.6 ± 16.5%, P < 0.05) was completely blocked 60 min after DAMGO microinjections ( n = 6; Δ10.2 ± 3.5%, P < 0.05). Furthermore, DAMGO pretreatment attenuated the increase in blood glucose levels after 2-DG infusion ( n = 6; 6.1 ± 0.7mmol/l vs. baseline 5.2 ± 0.3mmol/l, P > 0.05) compared with 2-DG alone ( n = 6; 7.6 ± 0.4mmol/l vs. baseline 6.0 ± 0.4mmol/l, P < 0.05). Thus, activation of RVLM µ-opioid receptors attenuated the neural efferent response to glucoprivation and reduced glucose production.

Cardiovascular effects of opioid antagonist naloxone in rostral ventrolateral medulla of rabbits

1990 ◽  
Vol 258 (2) ◽  
pp. R325-R331 ◽  
Author(s):  
D. A. Morilak ◽  
G. Drolet ◽  
J. Chalmers
Keyword(s):  
Pressor Response ◽  
Cardiovascular Effects ◽  
Rostral Ventrolateral Medulla ◽  
Endogenous Opioids ◽  
Opioid Antagonist ◽  
Ventrolateral Medulla ◽  
Inhibitory Influence ◽  
Beneficial Effects ◽  
Arterial Blood ◽  
Depressor Effect

We have examined the influence of endogenous opioids on the basal and reflex control of arterial blood pressure in the pressor region of the rostral ventrolateral medulla (RVLM) of chloralose-anesthetized rabbits. We tested basal effects both in intact animals and after hypotensive hemorrhage. Bilateral administration of the opiod antagonist naloxone (20 nmol, 100 nl) directly into the RVLM induced a gradual and prolonged increase in mean arterial pressure (MAP) (+17 +/- 2 mmHg). This was preceded by a brief and mild depressor effect (-9 +/- 3 mmHg), which was attributable to a transient reduction in excitability immediately after naloxone injection. When naloxone was administered into the RVLM after hemorrhage (20 ml/kg), it improved recovery of MAP relative to saline controls, again producing a gradual, prolonged pressor response (+29 +/- 5 mmHg). The effect of naloxone on a baroreflex in intact animals was only transient, with a brief, nonsignificant attenuation of the reflex depressor response to aortic nerve stimulation. We conclude that endogenous opioids exert a tonic inhibitory influence on RVLM pressor neurons and that this input remains active after hemorrhage. The RVLM may thus be one site for the beneficial effects of naloxone in preventing circulatory decompensation after hemorrhage. In contrast, opioid neurons are not an essential component of baroreflex-mediated sympathoinhibition in the RVLM.

Entrainment pattern between sympathetic and phrenic nerve activities in the Sprague-Dawley rat: hypoxia-evoked sympathetic activity during expiration

2004 ◽  
Vol 286 (6) ◽  
pp. R1121-R1128 ◽  
Author(s):  
Thomas E. Dick ◽  
Y.-H. Hsieh ◽  
Shaun Morrison ◽  
Sharon K. Coles ◽  
Nanduri Prabhakar
Keyword(s):  
Phrenic Nerve ◽  
Sympathetic Activity ◽  
Respiratory Pattern ◽  
Sprague Dawley ◽  
Short Term ◽  
Nerve Activity ◽  
Term Potentiation ◽  
Motor Activities ◽  
Respiratory Modulation ◽  
Activity Dependent

Sympathetic and respiratory motor activities are entrained centrally. We hypothesize that this coupling may partially underlie changes in sympathetic activity evoked by hypoxia due to activity-dependent changes in the respiratory pattern. Specifically, we tested the hypothesis that sympathetic nerve activity (SNA) expresses a short-term potentiation in activity after hypoxia similar to that expressed in phrenic nerve activity (PNA). Adult male, Sprague-Dawley (Zivic Miller) rats ( n = 19) were anesthetized (Equithesin), vagotomized, paralyzed, ventilated, and pneumothoracotomized. We recorded PNA and splanchnic SNA (sSNA) and generated cycle-triggered averages (CTAs) of rectified and integrated sSNA before, during, and after exposures to hypoxia (8% O2 and 92% N2 for 45 s). Inspiration (I) and expiration (E) were divided in half, and the average and area of integrated sSNA were calculated and compared at the following time points: before hypoxia, at the peak breathing frequency during hypoxia, immediately before the end of hypoxia, immediately after hypoxia, and 60 s after hypoxia. In our animal model, sSNA bursts consistently followed the I-E phase transition. With hypoxia, sSNA increased in both halves of E, but preferentially in the second rather than the first half of E, and decreased in I. After hypoxia, sSNA decreased abruptly, but the coefficient of variation in respiratory modulation of sSNA was significantly less than that at baseline. The hypoxic-evoked changes in sympathetic activity and respiratory pattern resulted in sSNA in the first half of E being correlated negatively to that in the second half of E ( r = −0.65, P < 0.05) and positively to Te ( r = 0.40, P < 0.05). Short-term potentiation in sSNA appeared not as an increase in the magnitude of activity but as an increased consistency of its respiratory modulation. By 60 s after hypoxia, the variability in the entrainment pattern had returned to baseline. The preferential recruitment of late expiratory sSNA during hypoxia results from either activation by expiratory-modulated neurons or by non-modulated neurons whose excitatory drive is not gated during late E.

scholarly journals Hypertension in Patients with Neurovascular Compression Is Associated with Increased Central Sympathetic Outflow

2002 ◽  
Vol 13 (1) ◽  
pp. 35-41
Author(s):  
Hans P. Schobel ◽  
Helga Frank ◽  
Ramin Naraghi ◽  
Helmut Geiger ◽  
Elmar Titz ◽  
...  
Keyword(s):  
Essential Hypertension ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Cold Pressor Test ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Neurovascular Compression ◽  
Sympathetic Outflow ◽  
Nerve Activity ◽  
Central Sympathetic Outflow

ABSTRACT. Recent data suggest a causal relationship between essential hypertension and neurovascular compression (NVC) at the rostral ventrolateral medulla. An increase of central sympathetic outflow might be an underlying pathomechanism. The sympathetic nerve activity to muscle was recorded in 21 patients with hypertension with NVC (NVC+ group) and in 12 patients with hypertension without NVC (NVC− group). Heart rate variability, respiratory activity, BP, and central venous pressure at rest and during unloading of cardiopulmonary baroreceptors with lower-body negative pressure and during a cold pressor test were also measured. Resting sympathetic nerve activity to muscle was twice as high in the NVC+ group compared with the NVC− group (34 ± 22 versus 18 ± 6 bursts/min; P < 0.05). Resting heart rate (P = 0.06) and low- to high-frequency power ratio values (P = NS) (as indicators of cardiac sympathovagal balance) tended to be augmented as well in the NVC+ group. The sympathetic nerve activity to muscle response to the cold pressor test was increased in the NVC+ group versus the NVC− group (+15 ± 11 versus 6 ± 12 bursts/min; P = 0.05), but hemodynamic and sympathetic nerve responses to lower-body negative pressure did not differ between the two groups. It is concluded that NVC of the rostral ventrolateral medulla in patients with essential hypertension is accompanied by increased central sympathetic outflow. Therefore, these data support the hypothesis described in the literature: in a subgroup of patients, essential hypertension might be causally related to NVC of the rostral ventrolateral medulla, at least in part, via an increase in central sympathetic outflow.

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