scholarly journals Blocking the transient receptor potential vanilloid-1 does not reduce the exercise pressor reflex in healthy rats

2019 ◽  
Vol 317 (4) ◽  
pp. R576-R587 ◽  
Author(s):  
Guillaume P. Ducrocq ◽  
Juan A. Estrada ◽  
Joyce S. Kim ◽  
Marc P. Kaufman
Keyword(s):  
Transient Receptor Potential ◽  
Pressor Response ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Triceps Surae ◽  
Transient Receptor Potential Vanilloid ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex ◽  
Transient Receptor ◽  
Target Effects

Controversy exists regarding the role played by transient receptor potential vanilloid-1 (TRPV1) in evoking the exercise pressor reflex. Here, we determine the role played by TRPV1 in evoking this reflex while assessing possible confounding factors arising from TRPV1 antagonists or from the vehicle in which they were dissolved. The exercise pressor reflex was evoked in decerebrated, anesthetized Sprague-Dawley rats by electrical stimulation of the tibial nerve to contract the triceps surae muscles statically. This procedure was repeated before and after injection of the TRPV1 blockers: capsazepine (100 μg/100 μL), ruthenium red (100 μg/100 μL), or iodoresiniferatoxin (IRTX; 1 μg/100 μL). We found that capsazepine decreased the exercise pressor reflex when the drug was dissolved in DMSO (−10 ± 9 mmHg; P = 0.015; n = 7). However, similar reduction was found when DMSO alone was injected (−8 ± 5 mmHg; P = 0.023; n = 5). Capsazepine, dissolved in ethanol (2 ± 6 mmHg; P = 0.49; n = 7), ruthenium red (−4 ± 12 mmHg; P = 0.41; n = 7), or IRTX (4 ± 18 mmHg; P = 0.56; n = 7), did not significantly decrease the exercise pressor reflex. In addition, we found that capsazepine and ruthenium red had “off-target” effects. Capsazepine decreased the pressor response evoked by intra-arterial injection of bradykinin (500 ng/kg; −12 ± 13 mmHg; P = 0.028; n = 9) and α-β-methylene ATP (10 μg/kg; −7 ± 8 mmHg; P = 0.019; n = 10), whereas ruthenium red decreased the ability of the muscle to produce and sustain force (−99 ± 83 g; P = 0.020; n = 7). Our data therefore suggest that TRPV1 does not play a role in evoking the exercise pressor reflex. Additionally, given their strong off-target effects, capsazepine and ruthenium red should not be used for studying the role played by TRPV1 in evoking the exercise pressor reflex.

scholarly journals Chronic femoral artery occlusion augments exercise pressor reflex in decerebrated rats

2010 ◽  
Vol 299 (1) ◽  
pp. H106-H113 ◽  
Author(s):  
Hirotsugu Tsuchimochi ◽  
Jennifer L. McCord ◽  
Shawn G. Hayes ◽  
Satoshi Koba ◽  
Marc P. Kaufman
Keyword(s):  
Femoral Artery ◽  
Transient Receptor Potential ◽  
Pressor Response ◽  
Arterial Occlusion ◽  
Receptor Potential ◽  
Artery Occlusion ◽  
Transient Receptor Potential Vanilloid ◽  
Hindlimb Muscles ◽  
Pressor Reflex ◽  
Transient Receptor

In decerebrated rats, we determined the pressor and cardioaccelerator reflex responses to static contraction of hindlimb muscles whose femoral arteries were either occluded 72 h before contraction, occluded 3 min before contraction, or freely perfused. We found that the pressor reflex arising from the limb whose femoral artery was occluded for 72 h before contraction (32 ± 5 mmHg, n = 16) was significantly higher than the pressor reflex arising from the contralateral freely perfused limb (15 ± 3 mmHg, n = 16, P < 0.001) or than that arising from the contralateral limb whose femoral artery was occluded for only 3 min (17 ± 4 mmHg, n = 16, P < 0.001). Moreover, the pressor reflex arising from the limb whose femoral artery was occluded for 3 min before the start of contraction was not significantly different than that arising from the contralateral freely perfused limb ( n = 16, P = 0.819). The pressor component of the reflex arising from the limb whose femoral artery was occluded for 72 h was not changed by transient receptor potential vanilloid (TRPV) 1 receptor blockade with iodo-resiniferatoxin ( n = 15, P = 0.272), although the cardioaccelerator component was significantly reduced ( P = 0.005). In addition, the pressor response evoked by capsaicin injection in the femoral artery of the 72-h occluded limb was more than double that evoked from the freely perfused limb ( P = 0.026). We conclude that chronic (i.e., 72 h) but not acute (3 min), femoral arterial occlusion augments pressor reflex arising from contraction of hindlimb muscles and that TRPV1 receptors play little role in this augmentation.

PLA2 and TRPV4 channels regulate endothelial calcium in cerebral arteries

2007 ◽  
Vol 292 (3) ◽  
pp. H1390-H1397 ◽  
Author(s):  
Sean P. Marrelli ◽  
Roger G. O'Neil ◽  
Rachel C. Brown ◽  
Robert M. Bryan
Keyword(s):  
Transient Receptor Potential ◽  
Cerebral Arteries ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Middle Cerebral Arteries ◽  
Trpv Channels ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
Trpv4 Channel

We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA2. In this study we examined possible mechanisms by which PLA2 regulates endothelium-dependent dilation, specifically whether PLA2 is involved in endothelial Ca2+ regulation through stimulation of TRPV4 channels. Studies were carried out with middle cerebral arteries (MCA) or freshly isolated MCA endothelial cells (EC) of male Long-Evans rats. Nitro-l-arginine methyl ester (l-NAME) and indomethacin were present throughout. In pressurized MCA, luminally delivered UTP produced increased EC intracellular Ca2+ concentration ([Ca2+]i) and MCA dilation. Incubation with PACOCF3, a PLA2 inhibitor, significantly reduced both EC [Ca2+]i and dilation responses to UTP. EC [Ca2+]i was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca2+ influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA2-sensitive Ca2+ influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA2 and a demonstrated activator of certain TRPV channels, increased both EC [Ca2+]i and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4α-phorbol 12,13-didecanoate (4αPDD), a TRPV4 channel activator, produced an increase in EC [Ca2+]i that was significantly reduced in the presence of ruthenium red. We conclude that PLA2 is involved in EC Ca2+ regulation through its regulation of TRPV4 channels. Furthermore, the PLA2-sensitive component of Ca2+ influx may be polarized to the abluminal face of the endothelium.

Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors

2006 ◽  
Vol 291 (3) ◽  
pp. R541-R550 ◽  
Author(s):  
Dan Ni ◽  
Qihai Gu ◽  
Hong-Zhen Hu ◽  
Na Gao ◽  
Michael X. Zhu ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Thermal Sensitivity ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive ◽  
Inward Current ◽  
Transient Receptor ◽  
Increasing Temperature

A recent study has demonstrated that increasing the intrathoracic temperature from 36°C to 41°C induced a distinct stimulatory and sensitizing effect on vagal pulmonary C-fiber afferents in anesthetized rats ( J Physiol 565: 295–308, 2005). We postulated that these responses are mediated through a direct activation of the temperature-sensitive transient receptor potential vanilloid (TRPV) receptors by hyperthermia. To test this hypothesis, we studied the effect of increasing temperature on pulmonary sensory neurons that were isolated from adult rat nodose/jugular ganglion and identified by retrograde labeling, using the whole cell perforated patch-clamping technique. Our results showed that increasing temperature from 23°C (or 35°C) to 41°C in a ramp pattern evoked an inward current, which began to emerge after exceeding a threshold of ∼34.4°C and then increased sharply in amplitude as the temperature was further increased, reaching a peak current of 173 ± 27 pA ( n = 75) at 41°C. The temperature coefficient, Q10, was 29.5 ± 6.4 over the range of 35–41°C. The peak inward current was only partially blocked by pretreatment with capsazepine (Δ I = 48.1 ± 4.7%, n = 11) or AMG 9810 (Δ I = 59.2 ± 7.8%, n = 8), selective antagonists of the TRPV1 channel, but almost completely abolished (Δ I = 96.3 ± 2.3%) by ruthenium red, an effective blocker of TRPV1–4 channels. Furthermore, positive expressions of TRPV1–4 transcripts and proteins in these neurons were demonstrated by RT-PCR and immunohistochemistry experiments, respectively. On the basis of these results, we conclude that increasing temperature within the normal physiological range can exert a direct stimulatory effect on pulmonary sensory neurons, and this effect is mediated through the activation of TRPV1, as well as other subtypes of TRPV channels.

Abstract 326: TRPV2 Regulates Cardiomyocyte Function via Altering Ca 2+ Cycling

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Xiaoqian Gao ◽  
Sheryl Koch ◽  
Min Jiang ◽  
Nathan Robbins ◽  
Wenfeng Cai ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ventricular Myocytes ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Noxious Heat ◽  
Cardiac Tissues ◽  
Membrane Stretching ◽  
Transient Receptor

TRPV2 is a member of transient receptor potential vanilloid (TRPV) family. As a Ca 2+ channel, it can detect various stimuli such as noxious heat (>52°C), membrane stretching, as well as a number of exogenous chemicals, including probenecid, 2-aminoethoxydiphenyl borate, and lysophospholipids. TRPV2 has been found in many tissue types, including neuron and kidney, but the function of TRPV2 in the heart is poorly understood. Here we show TRPV2 is involved in the Ca 2+ cycling process and then regulates the function of the cardiomyocyte. We identified the mRNA expression of TRPV2 in the cardiac tissues of mice using real-time PCR. By performing echocardiography we found that administration of probenecid, a selective TRPV2 agonist, increased cardiac ejection fraction in mice. This positive inotropic effect of probenecid was also shown in Langendorff perfused mice hearts as increased peak +dP/dt. In isolated ventricular myocytes, we found that probenecid significantly increased myocyte fractional shortening in a dose-dependent manner, which was fully blocked by ruthenium red, a non-selective TRPV2 blocker. We also performed fluorescent studies to examine myocyte Ca 2+ cycling. We found that probenecid significantly increased Ca 2+ transient and resting-state Ca 2+ sparks and this effect was eliminated by ruthenium red. When Ca 2+ storage in sarcoplasmic reticulum (SR) was depleted with caffeine, and SR Ca 2+ reuptake was blocked by thapsigargin at the same time, probenecid did not show any effects in either Ca 2+ transient or Ca 2+ sparks. Our patch clamp experiments indicate that probenecid treatment does not trigger any significant transmembrane Ca 2+ influx. These results point to the important role of TRPV2 in regulating SR Ca 2+ release. In conclusion, TRPV2 activation may contribute to increased SR Ca 2+ release, leading to the enhancement of myocyte contractility. Thus, TRPV2 plays a potentially important role in controlling the cellular function of heart.

scholarly journals TRPV4 activation mediates flow-induced nitric oxide production in the rat thick ascending limb

2014 ◽  
Vol 307 (6) ◽  
pp. F666-F672 ◽  
Author(s):  
Pablo D. Cabral ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
No Production ◽  
Thick Ascending Limb ◽  
Different Types ◽  
Luminal Flow ◽  
Transient Receptor

Nitric oxide (NO) regulates renal function. Luminal flow stimulates NO production in the thick ascending limb (TAL). Transient receptor potential vanilloid 4 (TRPV4) is a mechano-sensitive channel activated by luminal flow in different types of cells. We hypothesized that TRPV4 mediates flow-induced NO production in the rat TAL. We measured NO production in isolated, perfused rat TALs using the fluorescent dye DAF FM. Increasing luminal flow from 0 to 20 nl/min stimulated NO from 8 ± 3 to 45 ± 12 arbitrary units (AU)/min ( n = 5; P < 0.05). The TRPV4 antagonists, ruthenium red (15 μmol/l) and RN 1734 (10 μmol/l), blocked flow-induced NO production. Also, luminal flow did not increase NO production in the absence of extracellular calcium. We also studied the effect of luminal flow on NO production in TALs transduced with a TRPV4shRNA. In nontransduced TALs luminal flow increased NO production by 47 ± 17 AU/min ( P < 0.05; n = 5). Similar to nontransduced TALs, luminal flow increased NO production by 39 ± 11 AU/min ( P < 0.03; n = 5) in TALs transduced with a control negative sequence-shRNA while in TRPV4shRNA-transduced TALs, luminal flow did not increase NO production (Δ10 ± 15 AU/min; n = 5). We then tested the effect of two different TRPV4 agonists on NO production in the absence of luminal flow. 4α-Phorbol 12,13-didecanoate (1 μmol/l) enhanced NO production by 60 ± 11 AU/min ( P < 0.002; n = 7) and GSK1016790A (10 ηmol/l) increased NO production by 52 ± 15 AU/min ( P < 0.03; n = 5). GSK1016790A (10 ηmol/l) did not stimulate NO production in TRPV4shRNA-transduced TALs. We conclude that activation of TRPV4 channels mediates flow-induced NO production in the rat TAL.

Functional Expression of an Osmosensitive Cation Channel, Transient Receptor Potential Vanilloid 4, in Rat Vestibular Ganglia

2016 ◽  
Vol 21 (4) ◽  
pp. 268-274 ◽  
Author(s):  
Takefumi Kamakura ◽  
Makoto Kondo ◽  
Yoshihisa Koyama ◽  
Yukiko Hanada ◽  
Yusuke Ishida ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Expression ◽  
Ruthenium Red ◽  
Cation Channel ◽  
Trigeminal Ganglia ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv Channels ◽  
Polymerase Chain ◽  
Transient Receptor

Transient receptor potential vanilloid (TRPV) 4 is a nonselective cation channel expressed in sensory neurons such as those in the dorsal root and trigeminal ganglia, kidney, and inner ear. TRPV4 is activated by mechanical stress, heat, low osmotic pressure, low pH, and phorbol derivatives such as 4α-phorbol 12,13-didecanoate (4α-PDD). We investigated the expression of TRPV4 in rat vestibular ganglion (VG) neurons. The TRPV4 gene was successfully amplified from VG neuron mRNA using reverse-transcription polymerase chain reaction. Furthermore, immunoblotting showed positive expression of TRPV4 protein in VG neurons. Immunohistochemistry indicated that TRPV4 was localized predominantly on the plasma membrane of VG neurons. Calcium (Ca2+) imaging of VG neurons showed that 4α-PDD and/or hypotonic stimuli caused an increase in intracellular Ca2+ concentration ([Ca2+]i) that was almost completely inhibited by ruthenium red, a selective antagonist of TRPV channels. Interestingly, a [Ca2+]i increase was evoked by both hypotonic stimuli and 4α-PDD in approximately 38% of VG neurons. These data indicate that TRPV4 is functionally expressed in VG neurons as an ion channel and that TRPV4 likely participates in VG neurons for vestibular neurotransmission as an osmoreceptor and/or mechanoreceptor.

scholarly journals Transient Receptor Potential Vanilloid 5 Mediates Ca2+ Influx and Inhibits Chondrocyte Autophagy in a Rat Osteoarthritis Model

2017 ◽  
Vol 42 (1) ◽  
pp. 319-332 ◽  
Author(s):  
Yingliang Wei ◽  
Yanfang Wang ◽  
Yutong Wang ◽  
Lunhao Bai
Keyword(s):  
Articular Cartilage ◽  
Transient Receptor Potential ◽  
Joint Destruction ◽  
Receptor Potential ◽  
B Cell Lymphoma ◽  
Transient Receptor Potential Channel ◽  
Ruthenium Red ◽  
Protective Mechanism ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

Background: Autophagy, a self-protective mechanism of chondrocytes, has become a promising target to impede the progress of osteoarthritis (OA). Autophagy is regulated by cytosolic Ca2+ activity and may thus be modified by the Ca2+ permeable transient receptor potential channel vanilloid 5 (TRPV5). Therefore, we investigated the potential role of TRPV5 in mediating Ca2+ influx and in inhibiting chondrocyte autophagy in a rat OA model. Methods: The rat OA model was assessed by macroscopic and histological analyses. light chain 3B (LC3B) immunolocalization was detected by immunohistochemistry. TRPV5, LC3B and calmodulin in OA articular cartilage were assessed by real time polymerase chain reaction (RT-PCR) and western blotting. TRPV5 small interfering RNA (TRPV5 siRNA) were transfected into rat primary chondrocyte then the calmodulin and LC3B was detected by immunofluorescence. The functionality of the TRPV5 was assessed by Ca2+ influx. Western blot was used to measure autophagy-related proteins. Results: We constructed a monosodium iodoacetate (MIA) -induced rat OA model and found that ruthenium red (TRPV5 inhibitor) slowed the progression of joint destruction. We found that the TRPV5 and calmodulin were up-regulated but LC3B was down-regulated in articular cartilage following prolonged progression of OA. Furthermore, the up-regulated TRPV5 channel caused an increase in the Ca2+ influx in chondrocytes. The up-regulation of TRPV5 stimulated Ca2+ influx, which inhibited autophagy by increasing the production of calmodulin, phosphorylation of calmodulin dependent protein kinases II (p-CAMK II), phosphorylation of Beclin1 (p-Beclin1), and protein of B-cell lymphoma-2 (Bcl-2), and attenuating ratio of LC3-II/ LC3-. Conclusion: Up-regulated TRPV5 as an initiating factor inhibited chondrocyte autophagy via the mediation of Ca2+ influx.

scholarly journals Capsaicin-based analgesic balm attenuates the skeletal muscle metaboreflex in healthy humans

2018 ◽  
Vol 125 (2) ◽  
pp. 362-368 ◽  
Author(s):  
Lauro C. Vianna ◽  
Igor A. Fernandes ◽  
Thales C. Barbosa ◽  
André L. Teixeira ◽  
Antonio C. L. Nóbrega
Keyword(s):  
Transient Receptor Potential ◽  
Muscle Sympathetic Nerve Activity ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Isometric Handgrip ◽  
Muscle Metaboreflex ◽  
Exercise Pressor Reflex ◽  
Healthy Humans ◽  
Isometric Handgrip Exercise ◽  
Transient Receptor

The exercise pressor reflex (EPR) is comprised of group III and IV skeletal muscle afferents and is one of the principal mediators of the cardiovascular response to exercise. In animals, capsaicin-based analgesic balm (CAP) attenuates the pressor response to muscle contraction, indicating the transient receptor potential vanilloid 1 (TRPv1) receptor (localized on the group IV afferent neuron) as an important mediator of the EPR. However, whether these findings can be extrapolated to humans remains unknown. Here, we tested the hypothesis that CAP would attenuate blood pressure (BP) and muscle sympathetic nerve activity (MSNA) responses to isolated muscle metaboreflex activation in healthy men. MSNA (microneurography) and beat-to-beat heart hate (HR, by electrocardiography), and BP (finger photoplethysmography) were continuously measured in eight healthy males (23 ± 5 yr) at rest, during isometric handgrip exercise, and during postexercise ischemia (PEI). Trials were performed before and 30 and 60 min after the topical application of CAP (0.1%, CAPZASIN-HP) over the volar forearm of the subject’s exercising arm. Isometric exercise evoked increases in mean BP (∆32 ± 4 mmHg) and MSNA (∆26 ± 5 bursts/min; ∆19 ± 5 bursts/100 heart beats). The increases in BP during handgrip were not affected by CAP, but the increase in MSNA was lower after 60 min of CAP application. During PEI, the increases in BP and MSNA were all significantly less than those before CAP (all P < 0.05). In conclusion, CAP attenuated BP and sympathetic responses evoked by PEI in humans. These data provide evidence that transient receptor potential vanilloid 1 receptors potentially contribute to the EPR in humans, via its metabolic component. NEW & NOTEWORTHY We found that topical application of capsaicin-based analgesic balm attenuates arterial blood pressure and muscle sympathetic nerve activity during isolated muscle metaboreflex activation following isometric handgrip exercise in healthy humans. These findings suggest that the transient receptor potential vanilloid 1 may contribute to the exercise pressor reflex in humans via its metabolic component.

scholarly journals Expression profiles of TRPV1, TRPV4, TLR4 and ERK1/2 in the dorsal root ganglionic neurons of a cancer-induced neuropathy rat model

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4622 ◽  
Author(s):  
Ahmad Maqboul ◽  
Bakheet Elsadek
Keyword(s):  
Calcium Ions ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Expression Profiles ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Mechanical Hyperalgesia ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

Background The spread of tumors through neural routes is common in several types of cancer in which patients suffer from a moderate-to-severe neuropathy, neural damage and a distorted quality of life. Here we aim to examine the expression profiles of transient receptor potential vanilloid 1 (TRPV1) and of transient receptor potential vanilloid 4 (TRPV4), toll-like receptor 4 (TLR4) and extracellular signal-regulated kinase (ERK1/2), and to assess the possible therapeutic strategies through blockade of transient receptor potential (TRP) channels. Methods Cancer was induced within the sciatic nerves of male Copenhagen rats, and tissues from dorsal root ganglia (DRG) were collected and used for measurements of immunofluorescence and Western blotting. The TRPV1 antagonist capsazepine, the selective TRPV4 antagonist HC-067047 and the calcium ions inhibitor ruthenium red were used to treat thermal and/or mechanical hyperalgesia. Results Transient receptor potential vanilloid 1 showed a lower expression in DRGs on days 7 and 14. The expression of TRPV4, TLR4 and ERK1/2 showed an increase on day 3 then a decrease on days 7 and 14. TRPV1 and TLR4 as well as TRPV4 and ERK1/2 co-existed on the same neuronal cells. The neuropathic pain was reversed in dose-dependent manners by using the TRP antagonists and the calcium ions inhibitor. Conclusion The decreased expression of TRPV1 and TRPV4 is associated with high activation. The increased expression of TLR4 and ERK1/2 reveals earlier immune response and tumor progression, respectively, and their ultimate decrease is an indicator of nerve damage. We studied the possible role of TRPV1 and TRPV4 in transducing cancer-induced hyperalgesia. The possible treatment strategies of cancer-induced thermal and/or mechanical hyperalgesia using capsazepine, HC-067047 and ruthenium red are examined.

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