scholarly journals Intrathecal injection of brilliant blue G, a P2X7 antagonist, attenuates the exercise pressor reflex in rats

2020 ◽  
Vol 319 (2) ◽  
pp. R223-R232
Author(s):  
Juan A. Estrada ◽  
Guillaume P. Ducrocq ◽  
Joyce S. Kim ◽  
Marc P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Pressor Response ◽  
Intrathecal Injection ◽  
P2x Receptors ◽  
Brilliant Blue ◽  
Brilliant Blue G ◽  
P2x7 Receptors ◽  
P2x3 Receptors ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex

Purinergic 2X (P2X) receptors on the endings of group III and IV afferents play a role in evoking the exercise pressor reflex. Particular attention has been paid to P2X3 receptors because their blockade in the periphery attenuated this reflex. In contrast, nothing is known about the role played by P2X receptors in the spinal cord in evoking the exercise pressor reflex in rats. P2X7 receptors, in particular, may be especially important in this regard because they are found in abundance on spinal glial cells and may communicate with neurons to effect reflexes controlling cardiovascular function. Consequently, we investigated the role played by spinal P2X7 receptors in evoking the exercise pressor reflex in decerebrated rats. We found that intrathecal injection of the P2X7 antagonist brilliant blue G (BBG) attenuated the exercise pressor reflex (blood pressure index: 294 ± 112 mmHg·s before vs. 7 ± 32 mmHg·s after; P < 0.05). Likewise, intrathecal injection of minocycline, which inhibits microglial cell output, attenuated the reflex. In contrast, intrathecal injection of BBG did not attenuate the pressor response evoked by intracarotid injection of sodium cyanide, a maneuver that stimulated carotid chemoreceptors. Moreover, injections of BBG either into the arterial supply of the contracting hindlimb muscles or into the jugular vein did not attenuate the exercise pressor reflex. Our findings support the hypothesis that P2X7 receptors on microglial cells within the spinal cord play a role in evoking the exercise pressor reflex.

The exercise pressor reflex is attenuated by intrathecal oxytocin

1994 ◽  
Vol 267 (4) ◽  
pp. R909-R915 ◽  
Author(s):  
C. L. Stebbins ◽  
A. Ortiz-Acevedo
Keyword(s):  
Spinal Cord ◽  
Pressor Response ◽  
Intrathecal Injection ◽  
Sensory Nerve ◽  
Lumbar Spinal Cord ◽  
Exercise Pressor Reflex ◽  
Static Contraction ◽  
Before And After ◽  
Pressor Reflex ◽  
Lumbar Spinal

We tested the hypothesis that oxytocin (Oxt) acts in the lumbar spinal cord to attenuate reflex pressor (mean arterial pressure, MAP) and heart rate (HR) responses to static hindlimb contraction (i.e., the exercise pressor reflex). Thus we compared MAP and HR responses to electrically stimulated hindlimb static contraction in the anesthetized cat before and after intrathecal injection of Oxt (30 pmol, n = 3; 300 pmol, n = 6; or 3 nmol, n = 6). The 300-pmol dose was most effective; it attenuated the pressor response to static contraction by 39 +/- 10% but had no effect on HR. In three other cats, contraction-induced increases in MAP and HR were monitored before and after intrathecal injection of 300 pmol of Oxt + 300 nmol of the selective Oxt receptor antagonist [d(CH2)5(1),O-Me-Tyr2,Thr4,Tyr9,Orn8]vasotocin. Pretreatment with the antagonist eliminated the effect of Oxt on MAP. In an additional 10 cats, increases in these same variables in response to static contraction were compared before and after intrathecal injection of the Oxt antagonist (30 nmol, n = 3 or 300 nmol, n = 7) into the lumbar spinal cord (L1-L7). Whereas 30 nmol of the Oxt antagonist had no effect, the 300-nmol dose augmented the contraction-induced pressor and HR responses by 28 +/- 7 and 32 +/- 17%, respectively. These data imply that endogenous Oxt modulates the exercise pressor reflex by its action on Oxt receptors in the lumbar spinal cord that can attenuate sensory nerve transmission from skeletal muscle.

scholarly journals P2X2/3 and P2X3 receptors contribute to the metaboreceptor component of the exercise pressor reflex

2010 ◽  
Vol 109 (5) ◽  
pp. 1416-1423 ◽  
Author(s):  
Jennifer L. McCord ◽  
Hirotsugu Tsuchimochi ◽  
Marc P. Kaufman
Keyword(s):  
Pressor Response ◽  
P2x Receptors ◽  
Triceps Surae ◽  
P2x3 Receptor ◽  
P2x3 Receptors ◽  
Thin Fiber ◽  
Exercise Pressor Reflex ◽  
Metabolic Component ◽  
Pressor Reflex ◽  
Decerebrate Cats

The exercise pressor reflex is due to activation of thin fiber afferents within contracting muscle. These afferents are in part stimulated by ATP activation of purinergic 2X (P2X) receptors during contraction. Which of the P2X receptors contribute to the reflex is unknown; however, P2X2/3 and P2X3 receptor subtypes are good candidates because they are located on thin fiber afferents and are involved in sensory neurotransmission. To determine if P2X2/3 and P2X3 receptors evoke the metabolic component of the exercise pressor reflex, we examined the effect of two P2X2/3 and P2X3 antagonists, A-317491 (10 mg/kg) and RO-3 (10 mg/kg), on the pressor response to injections of α,β-methylene ATP (α,β-MeATP; 50 μg/kg), freely perfused static contraction, contraction of the triceps surae muscles while the circulation was occluded, and postcontraction circulatory occlusion in decerebrate cats. We found that the antagonists reduced the pressor response to α,β-MeATP injection (before Δ 20 ± 3 mmHg; drug Δ 11 ± 3 mmHg; P < 0.05), suggesting the antagonists were effective in blocking P2X2/3 and P2X3 receptors. P2X2/3 and P2X3 receptor blockade reduced the pressor response to freely perfused contraction (before Δ 33 ± 5 mmHg; drug Δ 15 ± 5 mmHg; P < 0.05), contraction with the circulation occluded (before Δ 52 ± 7 mmHg; drug Δ 20 ± 4 mmHg; P < 0.05), and during postcontraction circulatory occlusion (before Δ 15 ± 1 mmHg; drug Δ 5 ± 1 mmHg; P < 0.05). Our findings suggest that P2X2/3 and P2X3 receptors contribute to the metabolic component of the exercise pressor reflex in decerebrate cats.

Endogenous bradykinin in the thoracic spinal cord contributes to the exercise pressor reflex

1996 ◽  
Vol 81 (3) ◽  
pp. 1288-1294 ◽  
Author(s):  
C. L. Stebbins ◽  
S. Bonigut
Keyword(s):  
Spinal Cord ◽  
Heart Rate ◽  
Intrathecal Injection ◽  
Cardiovascular Responses ◽  
Left Ventricular ◽  
Thoracic Spinal Cord ◽  
Exercise Pressor Reflex ◽  
Thoracic Spinal ◽  
Pressor Reflex ◽  
Hoe 140

This investigation tested the hypothesis that bradykinin causes excitatory effects in the thoracic spinal cord that augment the exercise pressor reflex. Thus we performed 30 s of electrically stimulated static contraction of the hindlimb in the anesthetized cat (alpha-chloralose) to provoke reflex-induced increases in mean arterial pressure, maximal rate of rise of left ventricular pressure (dP/dt), and heart rate (i.e., the exercise pressor reflex). These three responses were compared before and 15 min after intrathecal injection of 2 micrograms (n = 3), 10 micrograms (n = 6), or 50 micrograms (n = 3) of the selective bradykinin B2- receptor antagonist HOE-140 into the thoracic spinal cord or 10 micrograms of this antagonist into the lumbar (n = 3) spinal cord. In three of the six cats in which 10 micrograms of HOE-140 were injected into the thoracic spinal cord, an additional contraction was performed 60-90 min after treatment. The 2-microgram dose of HOE-140 had no effect on the exercise pressor reflex. Injection of 10 micrograms of this antagonist into the thoracic spinal cord reduced the contraction-evoked pressor, maximal dP/dt, and heart rate responses by 49 +/-7, 58 +/- 4, and 64 +/- 13%, respectively (P < 0.05). Fifty micrograms of HOE-140 failed to attenuate these responses further. In the three cats in which an additional contraction was performed 60-90 min after treatment with 10 micrograms of the antagonist, blood pressure and dP/dt responses had returned, in part, toward initial values. Neither intravenous (n = 3) nor intrathecal injection of 10 micrograms of HOE-140 into the lumbar spinal cord had any effect on the contraction-induced cardiovascular responses. Thoracic injection of 50-200 ng of bradykinin provoked a pressor response of 26 +/- 5 mmHg that was abolished by a similar injection of 10 micrograms of HOE-140. These data suggest that endogenous bradykinin contributes to the exercise pressor reflex by an excitatory action in the thoracic spinal cord.

Role of NO in modulating neuronal activity in superficial dorsal horn of spinal cord during exercise pressor reflex

2002 ◽  
Vol 283 (3) ◽  
pp. H1012-H1018 ◽  
Author(s):  
Jianhua Li ◽  
Jere H. Mitchell
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Pressor Response ◽  
Triceps Surae ◽  
Superficial Dorsal Horn ◽  
Exercise Pressor Reflex ◽  
Fos Protein ◽  
Static Contraction ◽  
Pressor Reflex ◽  
Fos Expression

Static contraction of hindlimb skeletal muscle in cats induces a reflex pressor response. The superficial dorsal horn of the spinal cord is the major site of the first synapse of this reflex. In this study, static contraction of the triceps surae muscle was evoked by electrical stimulation of the tibial nerve for 2 min in anesthetized cats (stimulus parameters: two times motor threshold at 30 Hz, 0.025-ms duration). Ten stimulations were performed and 1-min rest was allowed between stimulations. Muscle contraction caused a maximal increase of 32 ± 5 mmHg in mean arterial pressure (MAP), which was obtained from the first three contractions. Activated neurons in the superficial dorsal horn were identified by c-Fos protein. Distinct c-Fos expression was present in the L6-S1 level of the superficial dorsal horn ipsilateral to the contracting leg (88 ± 14 labeled cells per section at L7), whereas only scattered c-Fos expression was observed in the contralateral superficial dorsal horn (9 ± 2 labeled cells per section, P < 0.05 compared with ipsilateral section). A few c-Fos-labeled cells were found in control animals (12 ± 5 labeled cells per section, P < 0.05 compared with stimulated cats). Furthermore, double-labeling methods demonstrated that c-Fos protein coexisted with nitric oxide (NO) synthase (NOS) positive staining in the superficial dorsal horn. Finally, an intrathecal injection of an inhibitor of NOS, N-nitro-l-arginine methyl ester (5 mM), resulted in fewer c-Fos-labeled cells (58 ± 12 labeled cells per section) and a reduced maximal MAP response (20 ± 3 mmHg, P < 0.05). These results suggest that the exercise pressor reflex induced by static contraction is mediated by activation of neurons in the superficial dorsal horn and that formation of NO in this region is involved in modulating the activated neurons and the pressor response to contraction.

Spinal estrogen attenuates the exercise pressor reflex but has little effect on the expression of genes regulating neurotransmitters in the dorsal root ganglia

2006 ◽  
Vol 100 (3) ◽  
pp. 958-964 ◽  
Author(s):  
Petra M. Schmitt ◽  
Kishorchandra Gohil ◽  
Marc P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Mrna Expression ◽  
Dorsal Root ◽  
Pressor Response ◽  
Muscle Afferents ◽  
Female Rats ◽  
Opioid Antagonist ◽  
Exercise Pressor Reflex ◽  
Static Contraction ◽  
Pressor Reflex

Previously, our laboratory showed that estrogen, topically applied to the spinal cord, attenuated the exercise pressor reflex in female cats (Schmitt PM and Kaufman MP. J Appl Physiol 95: 1418–1424, 2003; 98: 633–639, 2005). The attenuation was gender specific and was in part opioid dependent. Our finding that the μ- and δ-opioid antagonist naloxone was only able to partially restore estrogen’s attenuating effect on the pressor response to static contraction suggested that estrogen affected an additional pathway, involving the dorsal root ganglion (DRG). Estrogen has been described to stimulate transcription within 10 min of its application to the DRG, raising the possibility that rapid genomic effects on neurotransmitter production may have contributed to estrogen’s effect on the exercise pressor reflex. This prompted us to test the hypothesis that estrogen modulated the pressor response to static contraction by influencing gene expression of the neurotransmitters released by the thin-fiber muscle afferents that evoke the exercise pressor reflex. We confirmed in decerebrated female rats that topical application of estrogen (0.01 μg/ml) to the lumbosacral spinal cord attenuated the pressor response to static muscle contraction (from 10 ± 3 to 1 ± 1 mmHg; P < 0.05). DRG were then harvested postmortem, and changes in mRNA expression were analyzed. GeneChip analysis revealed that neither estrogen nor contraction alone changed the mRNA expression of substance P, the neurokinin-1 receptor, CGRP, NGF, the P2X3 receptor, GABAA and GABAB, the 5-HT3A and 5-HT3B receptor, N-methyl-d-aspartate and non- N-methyl-d-aspartate receptors, opioid receptors, and opioid-like receptor. Surprisingly, however, contraction stimulated the expression of neuropeptide Y in the DRG in the presence and absence of estrogen. We conclude that estrogen does not attenuate the exercise pressor reflex through a genomic effect in the DRG.

Estrogen attenuates the exercise pressor reflex in female cats

2003 ◽  
Vol 95 (4) ◽  
pp. 1418-1424 ◽  
Author(s):  
Petra M. Schmitt ◽  
M. P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Pressor Response ◽  
Muscle Afferents ◽  
Threshold Concentration ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Reflex Arc ◽  
17Β Estradiol ◽  
Pressor Reflex ◽  
The Difference

In humans, the pressor and muscle sympathetic nerve responses to static exercise are less in women than in men. The difference has been attributed to the effect of estrogen on the exercise pressor reflex. Estrogen receptors are abundant in areas of the dorsal horn receiving input from group III and IV muscle afferents, which comprise the sensory limb of the exercise pressor reflex arc. These findings prompted us to investigate the effect of estrogen on the spinal pathway of the exercise pressor reflex arc. Previously, we found that the threshold concentration of 17β-estradiol needed to attenuate the exercise pressor reflex in male decerebrate cats was 10 μg/ml (Schmitt PM and Kaufman MP. J Appl Physiol 94: 1431-1436, 2003). The threshold concentration for female cats, however, is not known. Consequently, we applied 17β-estradiol to a well covering the L6-S1 spinal cord in decerebrate female cats. The exercise pressor reflex was evoked by electrical stimulation of the L7 or S1 ventral root, a maneuver that caused the hindlimb muscles to contract statically. We found that the pressor response to contraction averaged 38 ± 7 mmHg before the application of 17β-estradiol (0.01 μg/ml) to the spinal cord, whereas it averaged only 23 ± 4 mmHg 30 min after application ( P < 0.05). Recovery of the pressor response to contraction was not obtained for 2 h after application of 17β-estradiol. Application of 17β-estradiol in a dose of 0.001 μg/ml had no effect on the exercise pressor reflex ( n = 5). We conclude that the concentration of 17β-estradiol required to attenuate the exercise pressor reflex is 1,000 times more dilute in female cats than that needed to attenuate this reflex in male cats.

Blockade of non-NMDA receptors attenuates reflex pressor response to static contraction

1994 ◽  
Vol 266 (5) ◽  
pp. H1769-H1776 ◽  
Author(s):  
J. M. Hill ◽  
J. G. Pickar ◽  
M. P. Kaufman
Keyword(s):  
Nmda Receptor ◽  
Substance P ◽  
Receptor Antagonist ◽  
Pressor Response ◽  
Intrathecal Injection ◽  
Ventilatory Responses ◽  
Exercise Pressor Reflex ◽  
Static Contraction ◽  
Substance P Receptor ◽  
Pressor Reflex

Considerable evidence suggests that both substance P and glutamate play a role in the spinal transmission of the exercise pressor reflex. We tested two hypotheses. First, after a lumbosacral intrathecal injection of a glutamatergic receptor antagonist, the reflex cardiovascular and ventilatory responses to static contraction are attenuated. Second, after a lumbosacral intrathecal injection of a substance P receptor antagonist and a glutamatergic receptor antagonist, the reflex cardiovascular and ventilatory responses to static contraction are abolished. We found that 1) the reflex cardiovascular responses to static contraction were unaffected (P > 0.05) after the intrathecal injection of the N-methyl-D-aspartate (NMDA) receptor antagonists, dl-2-amino-5-phosphonopentanoate (+/- AP-5) or 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (+/- CPP); 2) the reflex pressor response to static muscular contraction was attenuated by > 50% after the intrathecal injection of the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); and 3) the reflex pressor response to static contraction was almost abolished after the intrathecal injection of the substance P receptor antagonist, CP-96,345, and CNQX. Our results suggest that substance P and glutamate are two neurotransmitters involved in the spinal transmission of the exercise pressor reflex and that substance P and glutamate exert their effects via neurokinin-1 (NK-1) and non-NMDA receptors, respectively.

scholarly journals Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats

2013 ◽  
Vol 305 (1) ◽  
pp. R42-R49 ◽  
Author(s):  
Han-Jun Wang ◽  
Wei Wang ◽  
Kaushik P. Patel ◽  
George J. Rozanski ◽  
Irving H. Zucker
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Pressor Response ◽  
Central Component ◽  
Gaba A ◽  
Exercise Pressor Reflex ◽  
Dorsal Horns ◽  
Pressor Reflex

Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 μg/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR.

scholarly journals Glutamatergic receptor dysfunction in spinal cord contributes to the exaggerated exercise pressor reflex in heart failure

2015 ◽  
Vol 308 (5) ◽  
pp. H447-H455 ◽  
Author(s):  
Han-Jun Wang ◽  
Rebecca Cahoon ◽  
Edgar B. Cahoon ◽  
Hong Zheng ◽  
Kaushik P. Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Spinal Cord ◽  
Receptor Antagonist ◽  
Dorsal Horn ◽  
Pressor Response ◽  
Glutamate Release ◽  
Exercise Pressor Reflex ◽  
Dorsal Horns ◽  
Static Contraction ◽  
Pressor Reflex

Excitatory amino acids (e.g., glutamate) released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR) in physiological conditions. However, the role of glutamate and glutamate receptors in mediating the exaggerated EPR in the chronic heart failure (CHF) state remains to be determined. In the present study, we performed microinjection of glutamate receptor antagonists into ipisilateral L4/L5 dorsal horns to investigate their effects on the pressor response to static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots in decerebrate sham-operated (sham) and CHF rats. Microinjection of glutamate (10 mM, 100 nl) into the L4 or L5 dorsal horn caused a greater pressor response in CHF rats compared with sham rats. Furthermore, microinjection of either the broad-spectrum glutamate receptor antagonist kynurenate (10 mM, 100 nl) or the N-methyl-d-aspartate (NMDA) receptor antagonist dl-2-amino-5-phosphonovalerate (50 mM, 100 nl) or the non-NMDA-sensitive receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (5 mM, 100 nl) into L4/5 dorsal horns decreased the pressor response to static contraction in CHF rats to a greater extent than in sham rats. Molecular evidence showed that the protein expression of glutamate receptors (both non-NMDA and NMDA) was elevated in the dorsal horn of the lumbar spinal cord in CHF rats. In addition, data from microdialysis experiments demonstrated that although basal glutamate release at the dorsal horn at rest was similar between sham and CHF rats (225 ± 50 vs. 260 ± 63 nM in sham vs. CHF rats, n = 4, P > 0.05), CHF rats exhibit greater glutamate release into the dorsal horn during muscle contraction compared with sham rats (549 ± 60 vs. 980 ± 65 nM in sham vs. CHF rats, n = 4, P < 0.01). These data indicate that the spinal glutamate system contributes to the exaggerated EPR in the CHF state.

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