Published online before print September 22, 2008, doi: 10.1161/HYPERTENSIONAHA.108.114116
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2008;52:938.)
© 2008 American Heart Association, Inc.
Original Articles |
Mechanosensitive N-Methyl-D-Aspartate Receptors Contribute to Sensory Activation in the Rat Renal Pelvis
From the School of Medicine (M.-C.M.), Fu Jen Catholic University, Hsinchuang; the Department of Urology (H.-S.H.), National Taiwan University Hospital, Taipei; the Department of Cardiovascular Surgery (Y.-S.C.), National Taiwan University Hospital, Taipei; and the Department of Urology (S.-H.L.), Cardinal Tien Hospital, Hsintien, Taiwan.
Correspondence to Ming-Chieh Ma, 510 Chungcheng Road, School of Medicine, Fu Jen Catholic University, Hsinchuang 242, Taiwan. E-mail med0041{at}mail.fju.edu.tw or Shang-Hsing Lee, 362 Chungoheng Rd, Department of Urology, Cardinal Tien Hospital, Hsintien 231, Taiwan. E-mail sslee824.tw@yahoo.com.tw
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
The N-methyl-D-aspartate (NMDA) subtype of the ionotropic glutamate receptor is found in the periphery. The present study tested whether NMDA receptors (NMDARs) are present in the ends of afferent renal nerves in the renal pelvis, an area concerned mainly with transmitting sensation and the to reflex regulation of body fluid. The main NMDAR subunit, NMDA
1, was found to be more abundant in the renal pelvis than the renal cortex and medulla, and was mainly colocalized with the pan-neuronal marker PGP9.5 or the sensory nerve marker, the neurokinin-1 receptor. However, NMDA1 mRNA was undetectable, suggesting that it might be synthesized outside the renal pelvis. Intrarenal arterial administration of the specific ion channel blocker (+)-MK-801, but not the inactive enantiomer (–)-MK-801, decreased urine output and sodium excretion. High doses of (+)-MK-801 also caused regional vasoconstriction in the renal cortex, as determined by laser-Doppler flowmetry. Intrapelvic administration of the NMDAR ligand D-serine caused a dose-dependent increase in substance P (SP) release and afferent renal nerve activity, but had no effect on arterial pressure. The D-serine–induced sensory activation and SP release were abrogated by (+)-MK-801, the SP receptor blocker L-703,606, or dorsal rhizotomy. Increasing intrapelvic pressure resulted in an increase in afferent renal nerve activity and a diuretic/natriuretic response. Interestingly, these effects were attenuated by prior administration of (+)-MK-801. These results indicate that NMDAR-positive sensory nerves are present in the renal pelvis and contribute to the renorenal reflex control of body fluid.
Key Words: renal nerves • mechanoreceptors • kidney • reflex • diuresis • natriuresis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Mechanosensation is an important mechanism of signal transduction that mediates a number of biological processes ranging from the maintenance of cell volume to blood pressure regulation.1,2 Mechanically stimulating renal receptors through an increase in intrapelvic pressure (IPP) causes the release of sensory neuropeptides, such as substance P (SP), with consequent activation of afferent renal nerves.3–10 Increases in afferent renal nerve activity (ARNA) evoke an inhibitory renorenal reflex, which causes diuresis and natriuresis as a result of a reflex withdrawal of efferent renal sympathetic nerve activity.3–10 This reflex is seen not only when stimuli are directly applied to the kidney, but also during acute fluid expansion.8–10 Enhanced ARNA coincides with the increased IPP seen in association with extracellular volume expansion, indicating that an important role of ARNA is to sense the increased hydraulic pressure that occurs during massive urine formation. Intriguingly, defects in components of the SP system that cause poor sensory ability have been noted in a number of different animal models associated with fluid retention.4–10
Previous studies have shown that glutamate receptors are present in the peripheral tissues.11 The main subunit of the N-methyl-D-aspartate (NMDA) receptor, NMDA1, is present in the rat kidney.11–14 Activation of NMDARs by glycine evokes renal vasodilatation, which can be blocked by the specific receptor antagonist MK-801.13,14 Interestingly, inhibition of nitric oxide synthase (NOS) blocks NMDAR-mediated renal vasodilatation,15 suggesting that the receptor in the kidney is similar to that found in the central nervous system which induces Ca2+ influx and NOS activation. These results clearly reveal the important role of the NMDAR in the regulation of renal function. However, it is not known whether NMDARs affect renal sensory responses.
There is also evidence for a role of NMDARs in mechanical distention in internal organs, such as the stomach and colon.16,17 Furthermore, NMDARs in the Merkel cells of skin also contribute to the perception of mechanical stimuli during tactile sensation.18
Because of the existence of the NMDAR in the kidney and its unique role in sensing mechanical stimuli, we examined whether it is present in the renal pelvis and whether it contributes to the regulation of body fluid balance via the reflex function of afferent renal nerves. Understanding the role of NMDARs in the renal sensory response may help in elucidating the molecular mechanism associated with the pathogenesis of fluid retention, such as hypertension, and provide new therapeutic targets.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Female Wistar rats (Laboratory Animal Center, National Taiwan University, Taipei, Taiwan) weighing 200 to 220 g, were used. The experimental protocols were approved by the Institutional Animal Care and Use Committee.
Detection of NMDA1 and Serine Racemase in Renal Tissues
Rats were anesthetized with pentobarbital sodium (60 mg kg–1, IP) and the kidneys removed after transcardial perfusion as described previously.3,19
Western blotting was performed using antibodies (Santa Cruz) against rat NMDA1 (1:1000), serine racemase (SR) (1:1000), or actin (1:2000) as described previously.3,8–10 The negative control was staining with primary antibody preincubated with specific blocking peptide (Santa Cruz).
Semiquantitative RT-PCR20 was used to detect NMDA1 and SR mRNA using the appropriate primers. Details are available in the data supplement available online at http://hyper.ahajournals.org.
Immunohistochemistry was used to determine the intrarenal distribution of NMDA1, and indirect immunofluorescence was used to study the colocalization of NMDA1, PGP9.5, and the neurokinin-1 receptor (NK-1R) and the presence of SR in the renal pelvis as described previously.3,19
Intrarenal Effects of NMDAR Inhibition
Rats were anesthetized and cannulated as described previously.3 A PE-10 catheter with a fine tip was inserted into the left renal artery via the abdominal aorta and left femoral artery for intrarenal arterial (i.r.a.) infusion at a rate of 0.48 mL h–1. The left ureter was cannulated for collection of urine samples to determine the urinary flow rate (UV) and urinary sodium excretory rate (UNaV). Laser-Doppler flux (LDF) was monitored in the left renal cortex using a flowmeter (Transonic Systems). The infusion protocol consisted of a 10-minute baseline period of saline infusion, an experimental period of 5 consecutive 10-minute infusions of 1, 3, 10, 30, or 100 µg min–1 kg–1 of (+)-MK-801 or the inactive enantiomer (–)-MK-801 (both from Sigma), followed by a 10-minute recovery period of saline infusion (n=8 for each).
Renal Pelvic Perfusion
The rats were prepared as above. However, the left ureter was cannulated near the pelvis with a combined PE-10/50 catheter to allow renal pelvic perfusion, collection of effluent for SP assay, and recording of the IPP.3
Recording of Afferent Renal Nerve Activity
The techniques for recording and expressing multiunit renal nerve activity have been described.3,8–10
Effects of D-Serine on the Sensory Response
The infusion protocol consisted of a 10-minute baseline period of saline infusion, a 5-minute experimental period of intrapelvic infusion of 10, 30, or 100 µg mL–1 of D-serine randomly (Sigma, n=8 for each), and a 10-minute recovery period of saline infusion, MK-801 (10 µg min–1 kg–1, i.r.a.) being infused throughout.
Sensory responses were also examined during 5 minutes of intrapelvic infusion of 100 µg mL–1 of D-serine plus i.r.a. infusion of the SP receptor blocker L-703,606 (0.5 mg min–1 kg–1), plus intrapelvic infusion of 100 µg mL–1 of MK-801, and in rats with bilateral dorsal rhizotomy (DRX) at T9-L1 or sham-operated (Sham) rats after a 3-week induction period (n=8 for each).21 Measurements were made throughout each period and averaged.
Effects of NMDAR Inhibition on the Renorenal Reflex
Raising the IPP to 10, 20, or 50 mm Hg elicits renorenal reflexes.3,8–10 MK-801 (i.r.a. 10 µg min–1 kg–1 or intrapelvic 100 µg mL–1) was given 10 minutes before mechanostimulation and throughout the experiment (n=7 for each). The right ureter was cannulated for collection of the contralateral urine.
Renal Pelvic SP Release
SP was measured using an enzyme-linked immunoassay, as described previously.3,8–10
Statistical Analysis
Numeric data are presented as the mean±SEM. The Mann–Whitney U test, Friedman 2-way ANOVA, and a shortcut ANOVA were used to evaluate the effect of the drug or DRX on hemodynamic and excretory parameters, SP release, or ARNA responses to D-serine. Differences were regarded as significant at the level of P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Localization of NMDAR in Renal Tissues
Figure 1A shows that NMDA
1 was present in the rat kidney, being most abundant in the pelvis. In the cortex and medulla, NMDA1 was expressed, respectively, at 14±2 and 36±4% of renal pelvis levels. NMDA1 mRNA transcripts were undetectable in the renal pelvis of the 3 animals examined, but were present in the brain cortex positive control (Figure 1B).
|
NMDA1 was not homogenously distributed throughout the kidney, being found in the glomeruli, arteriole, and, to a lesser extent, in the tubules of the renal cortex and medulla (Figure 1C). In the renal pelvis, NMDA1 was found mainly in the fibrous structures between the uroepithelial and smooth muscle layers, and also just beneath the smooth muscle layer. Most nerve bundles in the renal pelvis contained NMDA1, as shown by double-labeling with antibodies against NMDA1 and a panneuronal (PGP9.5) or sensory nerve (NK-1R) marker (Figure 1D).
Intrarenal Effects of MK-801
Figure 2 shows the effects of i.r.a. infusion of MK-801. MK-801 had no significant effect on the mean arterial blood pressure (MABP), but (+)-MK-801 dose-dependently decreased the LDF at a dose of 30 or 100 µg min–1 kg–1 compared to the same dose of (–)-MK-801. (+)-MK-801 at 10, 30, or 100 µg min–1 kg–1 also significantly decreased the UV and UNaV, with maximal reduction at 30 µg min–1 kg–1. We therefore chose the dose of 10 µg min–1 kg–1 to study the effects on sensory function, as this dose lowered the UV and UNaV, but had no significant effect on the LDF.
|
D-Serine Induces Sensory Activation
As shown in Figure 3, i.r.a. or intrapelvic infusion of the test drugs did not affect the MABP or heart rate. Intrapelvic infusion of D-serine caused a dose-dependent increase in ARNA and SP release, which was blocked by i.r.a. infusion of (+)-MK-801, but not the (–)-MK-801 (left panel). The increase in ARNA, but not the increased SP release, caused by infusion of 100 µg ml–1 of D-serine was also blocked by i.r.a. infusion of L-703 606 (second panel from left) or intrapelvic infusion of (+)-MK-801 (third panel from left).
|
Significant difference (P<0.05) between the 2 treatments.DRX had no effect on the daily intake of food and water and body weight compared to sham-operated rats (data not shown), but blocked the ARNA increase and SP release seen after administration of 100 µg min–1 of D-serine (right panel).
NMDAR Inhibition Attenuates the Mechanostimulation-Induced Reflex Response
Figure 4 (left panel) shows the effects of mechanostimulation of the renal pelvis. During i.r.a. infusion of 10 µg min–1 kg–1 of (–)-MK-801, the MABP was unaffected by the 2 lower IPPs (10.5±1.4 and 20.6±1.8 mm Hg), but was significantly decreased at the high IPP (51.2±2.6 mm Hg), and the ARNA in the left kidney and the UV and UNaV of the contralateral kidney increased in an IPP-dependent manner. The same dose of (+)-MK-801 abolished the increases in the ipsilateral ARNA and contralateral diuretic/natriuretic response at IPP 10 mm Hg and the decrease in the MABP at IPP 50 mm Hg. Although the ARNA, UV, and UNaV were significantly increased at IPPs of 21.1±1.6 and 50.8±2.1 mm Hg in the presence of (+)-MK-801 (with the exception of the UV at IPP 20 mm Hg), these responses were largely attenuated compared to those when (–)-MK-801 was used (all P<0.05).
|
Intrapelvic infusion of 100 µg ml–1 of (+)-MK-801 also resulted in blockade of the IPP-induced renorenal reflex response at 
50 mm Hg (Figure 4, right panel).
Intrapelvic Expression of Serine Racemase
Figure 5A (left panel) shows that serine racemase (SR), the critical enzyme for the synthesis of D-serine,22 was expressed predominantly in, or below, the muscle layer of the renal pelvis, and, to a lesser extent, in the uroepithelial layer. Little fluorescence was seen in the negative control (right panel). Western blots showed that SR was distributed throughout the kidney and was more abundant in the renal pelvis and medulla (107±6% of renal pelvis level) than in the renal cortex (26±3% of renal pelvis level; Figure 5B). The expression pattern of SR mRNA was similar to that of protein expression (Figure 5C).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Figure 6 shows schematically, for the first time, evidence that NMDARs are present in the renal pelvis and sense increases in the IPP. It is interesting that the key enzyme responsible for synthesizing D-serine, SR, was also found in the renal pelvis. When the renal pelvic wall is stimulated by an increase in IPP, D-serine activates NMDARs, which act as mechanoreceptors, allowing SP to be released, possibly via a mechanism involving cation ion influx and sensory nerve activation. The important function of NMDARs as an initiator of renal sensory activation also has a profound effect on the reflex response, as NMDAR blockade reduced diuresis/natriuresis in the renorenal reflex and acute saline loading (please see http://hyper.ahajournals.org).
|
In the present study, we first examined the expression of NMDA1, as it is an obligatory subunit of NMDARs and essential for channel activity.13 However, NMDA
(NR2) is known to confer modulatory properties on receptors.13 Leung et al13 showed that NR2C protein, but not other NR2 subunits, are present in rat kidneys. Further studies are required to determine whether NMDA modulates receptor function in the ARNA response. The NMDA1 subunit was found to be unevenly distributed within the rat kidney. Although the vascular or tubular function of NMDARs is unknown, activation of NMDARs by glycine causes a vasodilatory response.14,15 Blockade of the NMDAR by (+)-MK-801 gradually reduced renal regional blood perfusion, supporting the idea that activation of NMDARs causes renal vasodilatation. Increased nitric oxide formation and activation of tubuloglomerular feedback have been postulated to contribute to NMDAR-mediated intrarenal vasodilation.14,15 Our results showed that the NMDA1 subunit was located in the cortical arterioles and glomeruli. This localization could directly affect glomerular perfusion or filtration via a vascular effect, as suggested previously.14,15 In a micropuncture study, Slomowitz et al23 showed that glycine infusion to activate NMDARs resulted in significant increases in the single-nephron GFR and blood flow which were attributable to significant decreases in afferent and efferent arteriolar resistance. We therefore speculate that intrarenal administration of (+)-MK-801 blocks receptor function in the arteriole and glomerulus and may cause a reduction in GFR.
We also showed that the low dose (10 µg min–1 kg–1) of (+)-MK-801 reduced renal excretion, with no effect on cortical perfusion. Increases in absolute proximal tubular reabsorption were also seen during glycine infusion by Slomowitz et al.23 This implies that (+)-MK-801 probably has a preferential effect on tubular reabsorption at a low dose and thus contributes to antinatriuresis and antidiuresis.
NMDA1 protein, but not mRNA, was found to be present in the renal pelvis, an area in which the NK-1R and SP are also expressed.3 The reason for the absence of NMDA1 mRNA is not known. However, Washbourne et al24 showed that NMDAR subunits are present in mobile transport packets and move rapidly along microtubules to axodendritic sites during synaptogenesis in rat cortical neurons. We therefore speculate that NMDA1 subunits may be synthesized in cell bodies in the dorsal root ganglia, then move to peripheral terminals via axonal transport.
Morphological studies have shown that NMDARs are present in unmyelinated and myelinated axons in the periphery.25,26 By calculating the conduction velocity of the single-unit ARNA, we showed that renal sensory nerves are C-fibers.3 This suggests that NMDARs are probably present in the unmyelinated C-fibers of afferent renal nerves. By monitoring the internalization of spinal SP receptors as an indirect measure of SP release, it has been shown that activation of presynaptic NMDARs facilitates SP release from primary afferents.27,28 Consistent with this, the present results showed that D-serine caused a dose-dependent increase in SP release. In addition to MK-801, an NK-1R blocker, and DRX also completely abolished D-serine–mediated sensory activation, suggesting that the functional presence of afferent renal nerves is necessary for NMDAR function and that the neurokinin system acts downstream of the NMDAR.
D-serine has been proposed as an endogenous agonist that binds to the glycine-binding site of the NMDA1 subunit.29 D-serine is up to 3- to 100-fold more effective than glycine in activating NMDARs expressed in hypoglossal motoneurons or recombinant receptors expressed in Xenopus oocytes.30,31 These results suggest that it might be a preferential agonist for NMDARs. With regard to the endogenous amount of D-serine, a previous study showed that, in some brain areas, extracellular levels of D-serine are similar to, or greater than, those of glycine, as determined by in vivo microdialysis.32 Furthermore, an important function of D-serine in the renal pelvis is strongly supported by our new observation of the presence of SR, the key enzyme in D-serine synthesis. SR is known to be present in human cardiac myocytes and the convoluted tubules of the kidney.33 These results strongly suggest a potential role for D-serine in the regulation of NMDAR activity in the kidney, especially in the renal pelvis.
There is considerable evidence that NMDARs present at the central end of primary afferent nerves modulate the baroreceptor reflex.34,35 However, stimulation or blockade of peripheral NMDARs causes hypotension or increases the blood pressure,36 suggesting that peripheral NMDARs are involved in the regulation of the systemic pressure. Kloda et al37 showed that membrane stretch exerted by either positive hydrostatic pressure or cytoskeletal deformation potentiates the NMDAR response and that membrane deformation frees the Mg2+ block on the NMDA channel, thus triggering Ca2+ influx. Although the in vivo range for pressure monitoring by NMDARs is not precisely known, the NMDAR contributes to responses of sensory afferent fibers innervating the distal stomach and colon during distension at pressures of 5 to 80 mm Hg.16,17 Consistent with this, the possible presence of NMDARs in renal C-fibers could detect a pressure range of 10 to 50 mm Hg. Moreover, our results showed that NMDARs detect an IPP range broader than that detected by the transient receptor potential vanilloid type 1 channel (TPRV1), another mechano-sensitive channel present in the renal pelvis.3 In contrast to TRPV1 inhibition,3 inhibition of NMDARs reduced the increase in ARNA seen at an IPP of 50 mm Hg.
In conclusion, our results clearly show that NMDARs in the renal pelvis monitor changes in IPP. The receptor profile includes stimulation by D-serine and inhibition by (+)-MK-801. SP release and NK-1R activation are essential for NMDAR-mediated sensory activation in the inhibitory renorenal reflex.
Perspectives
The discovery of mechanoreceptors in the renal pelvis has revealed that the kidney performs an important function in monitoring the intrarenal transmission of hydrostatic pressure from the beginning of the renal artery to the end of the renal tubule during urine formation. Activation of mechanoreceptors in afferent renal nerves triggers an inhibitory renorenal reflex and causes a diuretic and natriuretic response by reflex withdrawal of efferent renal sympathetic nerve activity.38 Impaired sensory function in the renorenal reflex can lead to abnormal fluid retention, particularly in various rat models of hypertension.4,5,39 As shown in this study, blockade of NMDARs attenuates urine excretion in the renorenal reflex. Moreover, inappropriate expression of NMDARs results in renal injury, as seen in gentamicin-induced nephrotoxicity.40 Thus, it is important to know whether altered function or expression of NMDARs is involved in the impaired renorenal reflex and excretory response in the pathogenesis of hypertension or other kidney diseases.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported by grants from the Cardinal Tien Hospital (CTH-94-1-2B01, CTH-96-1-2B02, CTH-98-1-2A27 to M.-C.M. and S.-H.L.) and the National Science Council of the Republic of China (NSC95-2320-B-030-006-MY2 to M.-C.M.).
Disclosures
None.
Received April 4, 2008; first decision April 24, 2008; accepted August 27, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Martinac B. Mechanosensitive ion channels: molecules of mechanotransduction. J Cell Sci. 2004; 117: 2449–2460.
2. Hamill OP. Twenty odd years of stretch-sensitive channels. Pflugers Arch. 2006; 453: 333–351.[CrossRef][Medline] [Order article via Infotrieve]
3. Feng NH, Lee HH, Shiang JC, Ma MC. Transient receptor potential vanilloid type 1 channels act as mechanoreceptors and cause substance P release and sensory activation in rat kidneys. Am J Physiol Renal Physiol. 2008; 294: F316–F325.
4. Kopp UC, Cicha MZ, Farley DM, Smith LA, Dixon BS. Renal substance P-containing neurons and substance P receptors impaired in hypertension. Hypertension. 1998; 31: 815–822.
5. Kopp UC, Smith LA. Bradykinin and protein kinase C activation fail to stimulate renal sensory neurons in hypertensive rats. Hypertension. 1996; 27: 607–612.
6. Kopp UC, Cicha MZ, Smith LA. Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin. Am J Physiol Regul Integr Comp Physiol. 2003; 284: R116–R124.
7. Gontijo JR, Smith LA, Kopp UC. CGRP activates renal pelvic substance P receptors by retarding substance P metabolism. Hypertension. 1999; 33: 493–498.
8. Ma MC, Huang HS, Chen CF. Impaired renal sensory responses after unilateral ureteral obstruction in the rat. J Am Soc Nephrol. 2002; 13: 1008–1016.
9. Ma MC, Huang HS, Chien CT, Wu MS, Chen CF. Temporal decrease in renal sensory responses in rats after chronic ligation of bile duct. Am J Physiol Renal Physiol. 2002; 138: F164–F172.
10. Ma MC, Huang HS, Wu MS, Chien CT, Chen CF. Impaired renal sensory responses after renal ischemia in the rat. J Am Soc Nephrol. 2002; 13: 1872–1883.
11. Hinoi E, Takarada T, Ueshima T, Tsuchihashi Y, Yoneda Y. Glutamate signaling in peripheral tissues. Eur J Biochem. 2004; 271: 1–13.[Medline] [Order article via Infotrieve]
12. Gill SS, Mueller RW, McGuire PF, Pulido OM. Potential target sites in peripheral tissues for excitatory neurotransmission and excitotoxicity. Toxicol Pathol. 2000; 28: 277–284.
13. Leung JC, Travis BR, Verlander JW, Sandhu SK, Yang SG, Zea AH, Weiner ID, Silverstein DM. Expression and developmental regulation of the NMDA receptor subunits in the kidney and cardiovascular system. Am J Physiol Regul Integr Comp Physiol. 2002; 283: R964–R971.
14. Deng A, Valdivielso JM, Munger KA, Blantz RC, Thomson SC. Vasodilatory N-methyl-D-aspartate receptors are constitutively expressed in rat kidney. J Am Soc Nephrol. 2002; 13: 1381–1384.
15. Blantz RC, Deng A, Lortie M, Munger K, Vallon V, Gabbai FB, Thomson SC. The complex role of nitric oxide in the regulation of glomerular ultrafiltration. Kidney Int. 2002; 61: 782–785.[CrossRef][Medline] [Order article via Infotrieve]
16. Sengupta JN, Petersen J, Peles S, Shaker R. Response properties of antral mechanosensitive afferent fibers and effects of ionotropic glutamate receptor antagonists. Neuroscience. 2004; 125: 711–723.[CrossRef][Medline] [Order article via Infotrieve]
17. Su X, Gebhart GF. Effects of tricyclic antidepressants on mechanosensitive pelvic nerve afferent fibers innervating the rat colon. Pain. 1998; 76: 105–114.[CrossRef][Medline] [Order article via Infotrieve]
18. Cahusac PM, Senok SS, Hitchcock IS, Genever PG, Baumann KI. Are unconventional NMDA receptors involved in slowly adapting type I mechanoreceptor responses? Neuroscience. 2005; 133: 763–773.[Medline] [Order article via Infotrieve]
19. Huang HS, Chen J, Chen CF, Ma MC. Vitamin E attenuates crystal formation in rat kidneys: Roles of renal tubular cell death and crystallization inhibitors. Kidney Int. 2006; 70: 699–710.[CrossRef][Medline] [Order article via Infotrieve]
20. Ma MC, Qian H, Ghassemi F, Zhao P, Xia Y. Oxygen sensitive 
-opioid receptor-regulated survival and death signals: novel insights into neuronal preconditioning and protection. J Biol Chem. 2005; 280: 16208–16218.
21. Lappe RW, Webb RL, Brody MJ. Selective destruction of renal afferent versus efferent nerves in rats. Am J Physiol. 1985; 249: R634–R637.[Medline] [Order article via Infotrieve]
22. Dumin E, Bendikov I, Foltyn VN, Misumi Y, Ikehara Y, Kartvelishvily E, Wolosker H. Modulation of D-serine levels via ubiquitin-dependent proteasomal degradation of serine racemase. J Bio Chem. 2006; 281: 20291–20302.
23. Slomowitz LA, Gabbai FB, Khang SJ, Satriano J, Thareau S, Deng A, Thomson SC, Blantz RC, Munger KA. Protein intake regulates the vasodilatory function of the kidney and NMDA receptor expression. Am J Physiol Regul Integr Comp Physiol. 2004; 287: R1184–R1189.
24. Washbourne P, Bennett JE, McAllister AK. Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nat Neurosci. 2002; 5: 751–759.[Medline] [Order article via Infotrieve]
25. Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett. 1995; 197: 25–28.[CrossRef][Medline] [Order article via Infotrieve]
26. Coggeshall RE, Carlton SM. Ultrastructural analysis of NMDA, AMPA, and kainate receptors on unmyelinated and myelinated axons in the periphery. J Comp Neurol. 1998; 391: 78–86.[CrossRef][Medline] [Order article via Infotrieve]
27. Liu H, Mantyh PW, Basbaum AI. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature. 1997; 386: 721–724.[CrossRef][Medline] [Order article via Infotrieve]
28. Marvizon JC, Martinez V, Grady EF, Bunnett NW, Mayer EA. Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. J Neurosci. 1997; 17: 8129–8136.
29. Parsons CG, Danysz W, Hesselink M, Hartmann S, Lorenz B, Wollenburg C, Quack G. Modulation of NMDA receptors by glycine-introduction to some basic aspects and recent developments. Amino Acids. 1998; 14: 207–216.[CrossRef][Medline] [Order article via Infotrieve]
30. Berger AJ, Dieudonne S, Ascher P. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol. 1998; 80: 3336–3340.
31. Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K. Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J Neurochem. 1995; 65: 454–458.[Medline] [Order article via Infotrieve]
32. Hashimoto A, Oka T, Nishikawa T. Extracellular concentration of endogenous free d-serine in the rat brain as revealed by in vivo microdialysis. Neurosci. 1995; 66: 635–643.[CrossRef][Medline] [Order article via Infotrieve]
33. Xia M, Liu Y, Figueroa DJ, Chiu CS, Wei N, Lawlor AM, Lu P, Sur C, Koblan KS, Connolly TM. Characterization and localization of a human serine racemase. Brain Res Mol Brain Res. 2004; 125: 96–104.[Medline] [Order article via Infotrieve]
34. Gordon FJ. Excitatory amino acid receptors in central cardiovascular regulation. Clin Exp Hypertens. 1995; 17: 81–90.[Medline] [Order article via Infotrieve]
35. Lo WC, Lin HC, Ger LP, Tung CS, Tseng CJ. Cardiovascular effects of nitric oxide and N-methyl-D-aspartate receptors in the nucleus tractus solitarii of rats. Hypertension. 1997; 30: 1499–1503.
36. Sitniewska EM, Wi
niewska RJ, Winiewski K. The role of ionotropic receptors of glutaminic acid in cardiovascular system. A. The influence of ionotropic receptor NMDA agonist-1R,3R-ACPD and antagonist-DL-AP7 on the systemic pressure in rats. Amino Acids. 2003; 24: 397–403.[CrossRef][Medline]
[Order article via Infotrieve]
37. Kloda A, Lua L, Hall R, Adams DJ, Martinac B. Liposome reconstitution and modulation of recombinant N-methyl-D-aspartate receptor channels by membrane stretch. Proc Natl Acad Sci U S A. 2007; 104: 1540–1545.
38. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997; 77: 75–197.
39. DiBona GF, Jones SY, Kopp UC. Renal mechanoreceptor dysfunction: an intermediate phenotype in spontaneously hypertensive rats. Hypertension. 1999; 33: 472–475.
40. Leung JC, Marphis T, Craver RD, Silverstein DM. Altered NMDA receptor expression in renal toxicity: protection with a receptor antagonist. Kidney Int. 2004; 66: 167–176.[CrossRef][Medline] [Order article via Infotrieve]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||