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Blocking the Transient Receptor Potential Vanilloid-1 Does Not Blocking the transient receptor potential vanilloid-1 does not reduce the exercise pressor reflex in healthy rats Guillaume Ducrocq, Juan Estrada, Joyce Kim, Marc Kaufman To cite this version: Guillaume Ducrocq, Juan Estrada, Joyce Kim, Marc Kaufman. Blocking the transient receptor po- tential vanilloid-1 does not reduce the exercise pressor reflex in healthy rats. AJP - Regulatory, Integrative and Comparative Physiology, American Physiological Society, 2019, 317 (4), pp.576 - 587. 10.1152/ajpregu.00174.2019. hal-02969591 HAL Id: hal-02969591 https://hal.archives-ouvertes.fr/hal-02969591 Submitted on 16 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Am J Physiol Regul Integr Comp Physiol 317: R576–R587, 2019. First published July 31, 2019; doi:10.1152/ajpregu.00174.2019. RESEARCH ARTICLE Neural Control Blocking the transient receptor potential vanilloid-1 does not reduce the exercise pressor reflex in healthy rats X Guillaume P. Ducrocq, Juan A. Estrada, X Joyce S. Kim, and Marc P. Kaufman Heart and Vascular Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Submitted 12 June 2019; accepted in final form 26 July 2019 Ducrocq GP, Estrada JA, Kim JS, Kaufman MP. Blocking the 28). Group III and IV muscle afferents synapse in laminae I, transient receptor potential vanilloid-1 does not reduce the exercise II, and V of the dorsal horn of the spinal cord (5, 26) and pressor reflex in healthy rats. Am J Physiol Regul Integr Comp Physiol then project to brainstem to exert their sympathoexcitatory 317: R576–R587, 2019. First published July 31, 2019; doi:10.1152/ effects (17). ajpregu.00174.2019.—Controversy exists regarding the role played Recently, studies have identified the receptors that activate by transient receptor potential vanilloid-1 (TRPV1) in evoking the exercise pressor reflex. Here, we determine the role played by TRPV1 the group III–IV afferent fibers, whose contraction-induced in evoking this reflex while assessing possible confounding factors stimulation evokes the exercise pressor reflex. So far, there is arising from TRPV1 antagonists or from the vehicle in which they good agreement that purinergic 2X receptors (15, 42), acid- were dissolved. The exercise pressor reflex was evoked in decere- sensing ion channels (42), and transient receptor potential brated, anesthetized Sprague-Dawley rats by electrical stimulation of (TRP) ankyrin-1 (23) play important roles in evoking the the tibial nerve to contract the triceps surae muscles statically. This reflex. In contrast, conflicting results exist regarding the role procedure was repeated before and after injection of the TRPV1 played by TRP vanilloid-1 (TRPV1) in evoking the exercise blockers: capsazepine (100 ␮g/100 ␮L), ruthenium red (100 ␮g/100 ␮ ␮ ␮ pressor reflex (22, 29, 38, 45). TRPV1 is expressed in rat dorsal L), or iodoresiniferatoxin (IRTX; 1 g/100 L). We found that root ganglion cells innervating the hindlimb muscles (29); it is capsazepine decreased the exercise pressor reflex when the drug was Ͻ Ͼ dissolved in DMSO (Ϫ10 Ϯ 9 mmHg; P ϭ 0.015; n ϭ 7). However, activated by low pH ( 5.5) and heat ( 43°C) and by vanilloid similar reduction was found when DMSO alone was injected (Ϫ8 Ϯ 5 compounds, such as capsaicin (4, 31). The hypothesis that mmHg; P ϭ 0.023; n ϭ 5). Capsazepine, dissolved in ethanol (2 Ϯ 6 TRPV1 plays a role in evoking the exercise pressor reflex may mmHg; P ϭ 0.49; n ϭ 7), ruthenium red (Ϫ4 Ϯ 12 mmHg; P ϭ 0.41; have arisen from findings that the injection of capsaicin into the n ϭ 7), or IRTX (4 Ϯ 18 mmHg; P ϭ 0.56; n ϭ 7), did not arterial supply of hindlimb skeletal muscle evoked a strong significantly decrease the exercise pressor reflex. In addition, we reflex pressor response (19, 47), an effect that, in turn, was found that capsazepine and ruthenium red had “off-target” effects. blunted by injection of TRPV1 antagonists (22, 38, 45). Two Capsazepine decreased the pressor response evoked by intra-arterial findings, however, cast doubt on this hypothesis, namely, that injection of bradykinin (500 ng/kg; Ϫ12 Ϯ 13 mmHg; P ϭ 0.028; n ϭ ␣ ␤ ␮ Ϫ Ϯ ϭ muscle interstitial pH does not decrease below 6.9 (43) and that 9) and - -methylene ATP (10 g/kg; 7 8 mmHg; P 0.019; during exhaustive exercise muscle temperature, does not in- n ϭ 10), whereas ruthenium red decreased the ability of the muscle to produce and sustain force (Ϫ99 Ϯ 83 g; P ϭ 0.020; n ϭ 7). Our data crease above 39°C (12). Furthermore, skeletal muscle does not therefore suggest that TRPV1 does not play a role in evoking the produce vanilloid substances (8). exercise pressor reflex. Additionally, given their strong off-target The lack of consensus regarding the role played by TRPV1 effects, capsazepine and ruthenium red should not be used for study- in evoking the exercise pressor reflex might have been caused ing the role played by TRPV1 in evoking the exercise pressor reflex. by differences in animal species (i.e., cats vs. rats), animal health, TRPV1 antagonists, and/or the solvents used to dissolve blood pressure; exercise; rats; transient receptor potential vanilloid-1 the antagonists. For example, the findings showing that cap- sazepine or iodoresiniferatoxin (IRTX) decreased the pressor response to static contraction have not been accompanied by INTRODUCTION the proper vehicle controls (29, 38), raising the possibility that the reduced pressor reflex found following capsazepine or The exercise pressor reflex, in combination with sympatho- IRTX injections was caused by the vehicle alone. In addition, lysis, functions to increase arterial blood flow to contracting the effect of TRPV1 antagonists might have been misinter- muscles (1, 32, 36). The afferent arm of the reflex is composed preted because of the drugs acting on other receptors. For of group III and IV fibers (25) whose endings are found in the example, capsazepine, in addition to inhibiting TRPV1 effec- interstitial space of skeletal muscle, small vessels, or connec- tively, has been found to inhibit voltage-gated calcium chan- tive tissue (40, 46a). For the most part, the endings of group III nels in vitro (10). Likewise, ruthenium red, acting as a nonse- afferents respond to mechanical distortion of their receptive lective TRP antagonist (2), also inhibits TRP ankyrin-1 (18), fields (20, 28, 33), whereas the endings of group IV afferents receptors that, in turn, have been shown to play a role in respond to byproducts of muscle contraction (20, 21, 27, evoking the exercise pressor reflex (23). In addition, ruthenium red blocks ryanodine receptors (48), an effect that might have reduced the ability of the muscle to produce force by reducing Address for reprint requests and other correspondence: G. P. Ducrocq, Heart 2ϩ and Vascular Institute, Pennsylvania State Univ. College of Medicine, 500 the sarcoplasmic release of Ca . It is therefore possible that University Dr., C2810, Hershey, PA 17033 (e-mail: [email protected]). the injection of TRPV1 antagonists might have reduced the R576 0363-6119/19 Copyright © 2019 the American Physiological Society http://www.ajpregu.org Downloaded from journals.physiology.org/journal/ajpregu (089.158.232.103) on May 6, 2020. TRPV1 AND THE EXERCISE PRESSOR REFLEX IN RATS R577 exercise pressor reflex by mechanisms other than just TRPV1 Animal Characteristics, Wellness, and Sample Size inhibition. Experiments were conducted at constant room air temperature Therefore, the main purpose of the present study was to (21°C) on 91 male Sprague-Dawley rats (Charles River), weighing determine the role played by TRPV1 in evoking the exercise 300–500 g. pressor reflex in healthy rats. To block TRPV1, we injected Rats were housed within the central animal facility of the Penn- capsazepine, ruthenium red, or IRTX into the arterial supply of sylvania State University College of Medicine, with access to food the triceps surae muscles. To determine if the vehicles in which and water ad libitum, and were exposed to a 50:50 light/dark cycle. these TRPV1 antagonists were dissolved affected the exercise All attempts were made to minimize animal discomfort and pain. pressor reflex, we tested the effect of dissolving capsazepine in two different solvents, namely, DMSO and ethanol. Finally, to Surgical Procedures determine possible confounding factors of TRPV1 antagonism, At the beginning of every surgery, the animal was anesthetized by we measured the effect of capsazepine on the pressor response ␣ ␤ inhalation of 4% of isoflurane with oxygen. We started the surgical evoked by bradykinin, - -methylene ATP, and diprotonated procedure only when the corneal reflex stopped and when pinching phosphate, each of which is a metabolic byproduct of contrac- the hindpaw did not produce a withdrawal reflex. tion but does not directly activate TRPV1. We also determined With the rat in supine position, the neck area was opened to expose the effect of ruthenium red on the ability of the muscle to the trachea, which was cannulated with a 2-cm long 14G Teflon tube. produce and sustain force. We tested the following hypotheses Lungs
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