scholarly journals Spinal P2X receptor modulates muscle pressor reflex via glutamate

2009 ◽  
Vol 106 (3) ◽  
pp. 865-870 ◽  
Author(s):  
Jianhua Li ◽  
Jian Lu ◽  
Zhaohui Gao ◽  
Satoshi Koba ◽  
Jihong Xing ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Pyridoxal Phosphate ◽  
Pressor Response ◽  
Cardiovascular Responses ◽  
P2x Receptors ◽  
P2x Receptor ◽  
Disulfonic Acid ◽  
Pressor Reflex ◽  
Stimulation Of

Static contraction of skeletal muscle evokes reflex increases in blood pressure and heart rate. Previous studies showed that P2X receptors located at the dorsal horn of the spinal cord play a role in modulating the muscle pressor reflex. P2X stimulation can alter release of the excitatory amino acid, glutamate (Glu). In this report, we tested the hypothesis that stimulation of P2X receptors enhances the concentrations of Glu ([Glu]) in the dorsal horn, and that blocking P2X receptors attenuates contraction-induced Glu increases and the resultant reflex pressor response. Contraction was elicited by electrical stimulation of the L7 and S1 ventral roots of 14 cats. Glu samples were collected from microdialysis probes inserted in the L7 level of the dorsal horn of the spinal cord, and dialysate [Glu] was determined using the HPLC method. First, microdialyzing α,β-methylene ATP (0.4 mM) into the dorsal horn significantly increased [Glu]. In addition, contraction elevated [Glu] from baseline of 536 ± 53 to 1,179 ± 192 nM ( P < 0.05 vs. baseline), and mean arterial pressure by 39 ± 8 mmHg in the control experiment. Microdialyzing the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (10 mM) into the dorsal horn attenuated the contraction induced-Glu increase (610 ± 128 to 759 ± 147 nM; P > 0.05) and pressor response (16 ± 3 mmHg, P < 0.05 vs. control). Our findings demonstrate that P2X modulates the cardiovascular responses to static muscle contraction by affecting the release of Glu in the dorsal horn of the spinal cord.

Spinal P2X receptor modulates reflex pressor response to activation of muscle afferents

2005 ◽  
Vol 288 (5) ◽  
pp. H2238-H2243 ◽  
Author(s):  
Zhaohui Gao ◽  
Valerie Kehoe ◽  
Lawrence I. Sinoway ◽  
Jianhua Li
Keyword(s):  
Dorsal Horn ◽  
Pressor Response ◽  
Cardiovascular Responses ◽  
P2x Receptors ◽  
Muscle Afferents ◽  
P2x Receptor ◽  
Reflex Response ◽  
Disulfonic Acid ◽  
Synaptic Site ◽  
Stimulation Of

Static contraction of skeletal muscle evokes increases in blood pressure and heart rate. Previous studies suggested that the dorsal horn of the spinal cord is the first synaptic site responsible for those cardiovascular responses. In this study, we examined the role of ATP-sensitive P2X receptors in the cardiovascular responses to contraction by microdialyzing the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) into the L7 level of the dorsal horn of nine anesthetized cats. Contraction was elicited by electrical stimulation of the L7 and S1 ventral roots. Blockade of P2X receptor attenuated the contraction induced-pressor response [change in mean arterial pressure (ΔMAP): 16 ± 4 mmHg after 10 mM PPADS vs. 42 ± 8 mmHg in control; P < 0.05]. In addition, the pressor response to muscle stretch was also blunted by PPADS (ΔMAP: 27 ± 5 mmHg after PPADS vs. 49 ± 8 mmHg in control; P < 0.05). Finally, activation of P2X receptor by microdialyzing 0.5 mM α,β-methylene into the dorsal horn significantly augmented the pressor response to contraction. This effect was antagonized by prior PPADS dialysis. These data demonstrate that blockade of P2X receptors in the dorsal horn attenuates the pressor response to activation of muscle afferents and that stimulation of P2X receptors enhances the reflex response, indicating that P2X receptors play a role in mediating the muscle pressor reflex at the first synaptic site of this reflex.

scholarly journals Purinergic 2X receptors play a role in evoking the exercise pressor reflex in rats with peripheral artery insufficiency

2014 ◽  
Vol 306 (3) ◽  
pp. H396-H404 ◽  
Author(s):  
Audrey J. Stone ◽  
Katsuya Yamauchi ◽  
Marc P. Kaufman
Keyword(s):  
Pyridoxal Phosphate ◽  
Pressor Response ◽  
P2x Receptors ◽  
P2x Receptor ◽  
Disulfonic Acid ◽  
Femoral Arteries ◽  
Exercise Pressor Reflex ◽  
Pressor Responses ◽  
Before And After ◽  
Pressor Reflex

Purinergic 2X (P2X) receptors on the endings of thin fiber afferents have been shown to play a role in evoking the exercise pressor reflex in cats. In this study, we attempted to extend this finding to decerebrated, unanesthetized rats whose femoral arteries were either freely perfused or were ligated 72 h before the start of the experiment. We first established that our dose of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 10 mg/kg), a P2X receptor antagonist, attenuated the pressor response to α,β-methylene ATP (10 μg/kg), a P2X receptor agonist. We then compared the exercise pressor reflex before and after infusing PPADS into the arterial supply of the hindlimb muscles that were statically contracted. In rats with freely perfused femoral arteries, the peak pressor responses to contraction were not significantly attenuated by PPADS (before PPADS: 19 ± 2 mmHg, 13 min after PPADS: 17 ± 2 mmHg, and 25 min after PPADS: 17 ± 3 mmHg). Likewise, the cardioaccelerator and renal sympathetic nerve responses were not significantly attenuated. In contrast, we found that in rats whose femoral arteries were ligated PPADS significantly attenuated the peak pressor responses to contraction (before PPADS: 37 ± 5 mmHg, 13 min after PPADS: 27 ± 6 mmHg, and 25 min after PPADS: 25 ± 5 mmHg; P < 0.05). Heart rate was not significantly attenuated, but renal SNA was at certain time points over the 30-s contraction period. We conclude that P2X receptors play a substantial role in evoking the exercise pressor reflex in rats whose femoral arteries were ligated but play only a minimal role in evoking the reflex in rats whose femoral arteries were freely perfused.

ATP stimulates chemically sensitive and sensitizes mechanically sensitive afferents

2002 ◽  
Vol 283 (6) ◽  
pp. H2636-H2643 ◽  
Author(s):  
Jianhua Li ◽  
Lawrence I. Sinoway
Keyword(s):  
Blood Pressure ◽  
Receptor Antagonist ◽  
Pyridoxal Phosphate ◽  
Pressor Response ◽  
P2x Receptors ◽  
Triceps Surae ◽  
P2x Receptor ◽  
Disulfonic Acid ◽  
Muscle Stretch ◽  
Arterial Blood

We examined whether ATP stimulation of P2X purinoceptors would raise blood pressure in decerebrate cats. Femoral arterial injection of the P2X receptor agonist α,β-methylene ATP into the blood supply of the triceps surae muscle induced a dose-dependent increase in arterial blood pressure. The maximal increase in mean arterial pressure (MAP) evoked by 0.1, 0.2, and 0.5 mM α,β-methylene ATP (0.5 ml/min injection rate) was 6.2 ± 2.5, 22.5 ± 4.4, and 35.2 ± 3.9 mmHg, respectively. The P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (2 mM ia) attenuated the increase in MAP elicited by intra-arterial α,β-methylene ATP (0.5 mM), whereas the P2Y receptor antagonist reactive blue 2 (2 mM ia) did not affect the MAP response to α,β-methylene ATP. In a second group of experiments, we tested the hypothesis that ATP acting through P2X receptors would sensitize muscle afferents and, thereby, augment the blood pressure response to muscle stretch. Two kilograms of muscle stretch evoked a 26.5 ± 4.3 mmHg increase in MAP. This MAP response was enhanced when 2 mM ATP or 0.1 mM α,β-methylene ATP (0.5 ml/min) was arterially infused 10 min before muscle stretch. Furthermore, this effect of ATP on the pressor response to stretch was attenuated by 2 mM pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid ( P < 0.05) but not by the P1 purinoceptor antagonist 8-( p-sulfophenyl)-theophylline (2 mM). These data indicate that activation of ATP-sensitive P2X receptors evokes a skeletal muscle afferent-mediated pressor response and that ATP at relatively low doses enhances the muscle pressor response to stretch via engagement of P2X receptors.

α,β-Methylene ATP elicits a reflex pressor response arising from muscle in decerebrate cats

2002 ◽  
Vol 93 (3) ◽  
pp. 834-841 ◽  
Author(s):  
Ramy L. Hanna ◽  
Shawn G. Hayes ◽  
Marc P. Kaufman
Keyword(s):  
Pyridoxal Phosphate ◽  
Pressor Response ◽  
P2 Receptors ◽  
Vascular Supply ◽  
Disulfonic Acid ◽  
Exercise Pressor Reflex ◽  
Pressor Responses ◽  
Chemical Stimuli ◽  
Pressor Reflex ◽  
Stimulation Of

In part, the exercise pressor reflex is believed to be evoked by chemical stimuli signaling that blood supply to exercising muscles is not adequate to meet its metabolic demands. There is evidence that either ATP or adenosine may function as one of these chemical stimuli. For example, muscle interstitial concentrations of both substances have been found to increase during exercise. This finding led us to test the hypothesis that popliteal arterial injection of α,β-methylene ATP (5, 20, and 50 μg/kg), which stimulates P2X receptors, and 2-chloroadenosine (25 μg/kg), which stimulates P1 receptors, evokes reflex pressor responses in decerebrate, unanesthetized cats. We found that popliteal arterial injection of the two highest doses of α,β-methylene ATP evoked pressor responses, whereas popliteal arterial injection of 2-chloroadenosine did not. In addition, the pressor responses evoked by α,β-methylene ATP were blocked either by section of the sciatic nerve or by prior popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (10 mg/kg), a selective P2-receptor antagonist. We conclude that the stimulation of P2 receptors, which are accessible through the vascular supply of skeletal muscle, evokes reflex pressor responses. In addition, our findings are consistent with the hypothesis that the stimulation of P2 receptors comprises part of the metabolic error signal evoking the exercise pressor reflex.

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.

Segmental effect of spinal NK-1 receptor blockade on the pressor reflex

1998 ◽  
Vol 275 (3) ◽  
pp. H789-H796 ◽  
Author(s):  
L. Britt Wilson ◽  
Gregory A. Hand
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Dorsal Horn ◽  
Dorsal Root ◽  
Pressor Response ◽  
Afferent Neurons ◽  
Muscle Stretch ◽  
Primary Afferent ◽  
Static Contraction ◽  
Pressor Reflex

The physiological effects of substance P (SP) are mediated via activation of neurokinin-1 (NK-1) receptors. The purpose of this study was to test the hypothesis that blockade of NK-1 receptors in the dorsal horn, both at the site of entry for the primary afferent neurons and adjacent spinal segments, attenuates the pressor reflex evoked by static contraction and stretch of skeletal muscle. Cats were anesthetized with α-chloralose and urethan, and a laminectomy was performed. With the exception of the L7 dorsal root, the dorsal and ventral roots from L5 to S2 were sectioned on one side of the spinal cord. Thus the primary afferent fibers mediating the pressor reflex enter the spinal cord via the L7 dorsal root in these experiments. Based on dose-response data, dialysis of the NK-1 receptor antagonist CP-96,345 (5 mM for 2 h) into the L7 dorsal horn ipsilateral to the contracting muscle attenuated the pressor response to static contraction (75 ± 15 vs. 46 ± 7 mmHg; n = 5 cats) but not muscle stretch (60 ± 12 vs. 50 ± 8 mmHg). Administration of the inactive enantiomer of CP-96,345, CP-96,344 (5 mM for 2 h), into the L7 dorsal horn failed to alter the cardiovascular changes elicited by contraction (45 ± 7 vs. 43 ± 6 mmHg) and stretch (31 ± 8 vs. 32 ± 11). Dialysis of 5 mM CP-96,345 into the dorsal horn at the L6 and S1 segments for 2 h decreased the peak pressor response to static contraction (58 ± 9 vs. 31 ± 6 mmHg; n = 7) and muscle stretch (61 ± 6 vs. 44 ± 8 mmHg). These data suggest that the activation of NK-1 receptors, both at the site of entry and in regions outside of the entry site for afferent neurons, is involved in the spinal processing that produces the pressor reflex evoked by static contraction of skeletal muscle.

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.

scholarly journals Cloning and characterization of a functional P2X receptor from larval bullfrog skin

2001 ◽  
Vol 281 (3) ◽  
pp. C954-C962 ◽  
Author(s):  
Philip J. Jensik ◽  
Doyle Holbird ◽  
Michael W. Collard ◽  
Thomas C. Cox
Keyword(s):  
Pyridoxal Phosphate ◽  
Rana Catesbeiana ◽  
Short Circuit ◽  
Short Circuit Current ◽  
P2x Receptors ◽  
P2x Receptor ◽  
Disulfonic Acid ◽  
Acid Protein ◽  
Sensory Reception ◽  
Tadpole Skin

ATP activates an apical-to-basolateral nonselective cation current across the skin of larval bullfrogs ( Rana catesbeiana) with similarities to currents carried by some P2X receptors. A functional P2X receptor was cloned from tadpole skin RNA that encodes a 409-amino acid protein with highest protein homology to cP2X8. RT-PCR showed that this transcript was found in skin, heart, eye, brain, and skeletal muscle of tadpoles but not in skin, brain, or heart of adults. After transcribed RNA from this clone was injected into Xenopus oocytes, application of ATP activated a transient current similar to other P2X receptors and the ATP-activated transient in short-circuit current ( I sc) across intact skin. The agonists 2-methylthio-ATP and adenosine-5′- O-(thiotriphoshate) also activated transient currents. α,β-Methylene-ATP and ADP were poor agonists of this receptor. Suramin and pyridoxal phosphate 6-azophenyl-2′,4′-disulfonic acid tetrasodium (PPADS) were potent antagonists, and PPADS showed an irreversible blockade of this receptor to agonist activation. Under external Na+-free, Ca2+/Mg2+-free conditions ( N-methyl-d-glucamine replacement, 0.5 mM EGTA), ATP activated a steadily increasing inward current. Fluorescence microscopy showed that propidium was entering the cells, suggesting that a relatively large pore size was formed under zero divalent conditions. This clone has some characteristics consistent with previously described ATP-activated I sc in the tadpole skin. Because the clone is not found in adult skin, it may have some exclusive role in the tadpole such as sensory reception by the skin or triggering apoptosis at metamorphosis.

P2X receptor-mediated muscle pressor reflex in myocardial infarction

2007 ◽  
Vol 292 (2) ◽  
pp. H939-H945 ◽  
Author(s):  
Zhaohui Gao ◽  
Jihong Xing ◽  
Lawrence Sinoway ◽  
Jianhua Li
Keyword(s):  
Myocardial Infarction ◽  
Blood Pressure ◽  
Pressor Response ◽  
P2x Receptors ◽  
P2x Receptor ◽  
Reflex Response ◽  
Lv Function ◽  
Drg Neurons ◽  
Muscle Afferent ◽  
Pressor Reflex

A previous report from this laboratory demonstrated that the ATP-sensitive P2X receptor-mediated muscle pressor reflex was augmented in rats with heart failure (HF). The purpose of this study was to better understand the underlying mechanisms for this greater response in HF rats. We examined 1) responsiveness of the P2X receptor to α,β-methylene ATP (α,β-me-ATP), a P2X receptor agonist, in control and HF rats induced by myocardial infarction (MI); 2) the relationship between P2X-induced blood pressure response and left ventricular (LV) function; and 3) the expression of P2X receptors in the dorsal root ganglion (DRG) of control rats and rats with HF. Eight to 14 wk after coronary artery ligation, the severity of the MI was determined by echocardiography. In the first group of the experiment, α,β-me-ATP (0.0625, 0.125, 0.25, and 0.5 mM) was injected into the arterial blood supply of the hindlimb muscles to evoke a pressor response in 17 decerebrated rats (6 controls, 6 small MIs with infarcts of the LV between 10 and 35%, and 5 large MIs with infarcts >35%). The P2X agonist increased blood pressure, and the effect was significantly accentuated in large MI rats compared with small MI rats and control rats. A significant correlation was observed between α,β-me-ATP-evoked pressor response and the LV fractional shortening, an index of LV function. In the second group of the experiment, immunocytochemistry was used to examine the immunoreactivity of P2X receptor in the DRG neurons of small diameter fibers in six healthy control rats, five small MI, and five large MI rats. The percentage of P2X immunostaining-positive neurons in the DRG was markedly greater in large MI rats (52% vs. 29% in controls and 34% in small MIs, P < 0.05). In conclusion, our findings demonstrate that 1) muscle afferent-mediated pressor response of P2X activation was exaggerated in MI animals, and the responsiveness was related to the degree of LV dysfunction; and 2) augmented reflex response was associated with upregulated P2X receptors in the DRG neurons of thin fiber afferent nerves following MI. The data suggest that P2X-mediated responsiveness in the processing of muscle afferent signals may have important implications for understanding cardiovascular responses to exercise in HF.

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