Skip to main content
SpringerLink
Log in

Investigating the involvement of TRPV1 ion channels in remote hind limb preconditioning-induced cardioprotection in rats

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Remote ischemic preconditioning (RIPC) treatment strategy is a breakthrough in the field of cardiovascular pharmacology as it has the potential to attenuate myocardial ischemia-reperfusion injury. However, the underlying intracellular pathways have not been widely explored. The present study intends to explore the possible role of TRPV1 channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 cycles in succession) was delivered by tying the blood pressure cuff at the inguinal level of the rat. The Langendorff system was used to perfuse the isolated heart and afterward was subjected to 30 min of global ischemia and 120 min of reperfusion. Sustained ischemia and, thereafter, reperfusion led to cardiac injury that was assessed in terms of infarct size, lactate dehydrogenase (LDH) release, creatine kinase (CK) release, left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), +dp/dtmax, −dp/dtmin, heart rate, rate pressure product, and coronary flow rate. The pharmacological modulators employed included capsaicin as TRPV1 agonist and capsazepine as TRPV1 antagonist. Remote hind limb preconditioning stimulus and capsaicin preconditioning (5 and 10 mg/kg) led to significant reduction in infarct size, LVEDP, LDH release, CK release, and significant improvement in LVDP, +dp/dtmax, −dp/dtmin, heart rate, rate pressure product, and coronary flow rate. However, remote hind limb preconditioning-induced cardioprotective effects were considerably abolished in the presence of capsazepine (2.5 and 5 mg/kg). This indicates that remote hind limb preconditioning stimulus possibly activates TRPV1 channels to produce cardioprotective effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Almeida V, Peres FF, Levin R, Suiama MA, Calzavara MB, Zuardi AW, Hallak JE, Crippa JA, Abílio VC (2014) Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: the SHR strain. Schizophr Res 153:150–159

    Article  PubMed  Google Scholar 

  • Bevan S, Hothi S, Hughes G, James IF, Rang HP, Shah K, Walpole CS, Yeats JC (1992) Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br J Pharmacol 107:544–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boillat A, Alijevic O, Kellenberger S (2014) Calcium entry via TRPV1 but not ASICs induces neuropeptide release from sensory neurons. Mol Cell Neurosci 61:13–22

  • Diwan V, Kant R, Jaggi AS, Singh N, Singh D (2008) Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem 315:195–201

    Article  CAS  PubMed  Google Scholar 

  • Eckert P, Schnackerz K (1991) Ischemic tolerance of human skeletal muscle. Ann Plast Surg 26:77–84

    Article  CAS  PubMed  Google Scholar 

  • Gao F, Liang Y, Wang X, Lu Z, Li L, Zhu S, Liu D, Yan Z, Zhu Z (2014) TRPV1 activation attenuates high-salt diet-induced cardiac hypertrophy and fibrosis through PPAR-δ upregulation. PPAR Res 2014:491963

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Song J, Chen H, Cao C, Lee C (2015) TRPV1 activation is involved in the cardioprotection of remote limb ischemic postconditioning in ischemia-reperfusion injury rats. Biochem Biophys Res Commun 463:1034–1039

    Article  CAS  PubMed  Google Scholar 

  • Guzy PM (1977) Creatine phosphokinase-MB (CPK-MB) and the diagnosis of myocardial infarction. West J Med 127:455–460

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hanson SM, Newstead S, Swartz KJ, Sansom MS (2015) Capsaicin interaction with TRPV1 channels in a lipid bilayer: molecular dynamics simulation. Biophys J 108:1425–1434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harper AG, Brownlow SL, Sage SO (2009) A role for TRPV1 in agonist-evoked activation of human platelets. J Thromb Haemost 7(2):330–8

  • Hazan A, Kumar R, Matzner H, Priel A (2015) The pain receptor TRPV1 displays agonist-dependent activation stoichiometry. Sci Rep 5:12278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herscher LL, Siegel RJ, Said JW, Edwalds GM, Moran MM, Fishbein MC (1984) Distribution of LDH-1 in normal, ischemic, and necrotic myocardium. An immunoperoxidase study. Am J Clin Pathol 81:198–203

    Article  CAS  PubMed  Google Scholar 

  • Inoue R, Jensen LJ, Shi J, Morita H, Nishida M, Honda A, Ito Y (2006) Transient receptor potential channels in cardiovascular function and disease. Circ Res 21(99):119–131

  • Kant R, Diwan V, Jaggi AS, Singh N, Singh D (2008) Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases. Mol Cell Biochem 312:25–31

    Article  CAS  PubMed  Google Scholar 

  • Kaszas K, Keller JM, Coddou C, Mishra SK, Hoon MA, Stojilkovic S, Jacobson KA, Iadarola MJ (2012) Small molecule positive allosteric modulation of TRPV1 activation by vanilloids and acidic pH. J Pharmacol Exp Ther 340:152–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khatibi NH, Jadhav V, Charles S, Chiu J, Buchholz J, Tang J, Zhang JH (2011) Capsaicin pre-treatment provides neurovascular protection against neonatal hypoxic-ischemic brain injury in rats. Acta Neurochir Suppl 111:225–230

    Article  PubMed  PubMed Central  Google Scholar 

  • King J (1959) A routine method for the estimation of lactic dehydrogenase activity. J Med Lab Technol 16:265–272

    CAS  PubMed  Google Scholar 

  • Langendorff O (1885) Untersuchungen amuber lebenderer saugethierherzen. Pfluger. Arch. Gesmate.Physio 61:291–332

  • Li D, Li NS, Chen QQ, Guo R, Xu PS, Deng HW, Li YJ (2008) Calcitonin gene-related peptide-mediated cardioprotection of postconditioning in isolated rat hearts. Regul Pept 147:4–8

    Article  CAS  PubMed  Google Scholar 

  • Lu MJ, Chen YS, Huang HS, Ma MC (2014) Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway. Basic Res Cardiol 109:414

    Article  PubMed  Google Scholar 

  • Newson PN, van den Buuse M, Martin S, Lynch-Frame A, Chahl LA (2014) Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour. Behav Brain Res 272:55–65

    Article  CAS  PubMed  Google Scholar 

  • Nishio R, Sasayama S, Matsumori A (2002) Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis. J Am Coll Cardiol 40:1506–1514

    Article  PubMed  Google Scholar 

  • Node K, Kitakaze M, Sato H, Minamino T, Komamura K, Shinozaki Y, Mori H, Hori M (1997) Role of intracellular Ca2+ in activation of protein kinase C during ischemic preconditioning. Circulation 96:1257–1265

    Article  CAS  PubMed  Google Scholar 

  • Nozadze I, Tsiklauri N, Gurtskaia G, Tsagareli MG (2016) Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats. Behav Pharmacol 27:29–36

    Article  CAS  PubMed  Google Scholar 

  • Peng J, Li YJ (2010) The vanilloid receptor TRPV1: role in cardiovascular and gastrointestinal protection. Eur J Pharmacol 627:1–7

    Article  CAS  PubMed  Google Scholar 

  • Preus M, Bhargava AS, Khater AE, Günzel P (1988) Diagnostic value of serum creatine kinase and lactate dehydrogenase isoenzyme determinations for monitoring early cardiac damage in rats. Toxicol Lett 42:225–233

    Article  CAS  PubMed  Google Scholar 

  • Randhawa PK, Jaggi AS (2015) TRPV1 and TRPV4 channels: potential therapeutic targets for ischemic conditioning-induced cardioprotection. Eur J Pharmacol 746:180–185

    Article  CAS  PubMed  Google Scholar 

  • Randhawa PK, Jaggi AS (2016) Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. Naunyn Schmiedeberg’s Arch Pharmacol 389(8):887–896

    Article  CAS  Google Scholar 

  • Reichelt ME, Willems L, Hack BA, Peart JN, Headrick JP (2009) Cardiac and coronary function in the Langendorff-perfused mouse heart model. Exp Physiol 94:54–70

    Article  CAS  PubMed  Google Scholar 

  • Serizawa T, Vogel WM, Apstein CS, Grossman W (1981) Comparison of acute alterations in left ventricular relaxation and diastolic chamber stiffness induced by hypoxia and ischemia. Role of myocardial oxygen supply-demand imbalance. J Clin Invest 68(1):91–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharif-Naeini R, Ciura S, Zhang Z, Bourque CW (2008) Contribution of TRPV channels to osmosensory transduction, thirst, and vasopressin release. Kidney Int 73:811–815

    Article  CAS  PubMed  Google Scholar 

  • Sharma R, Randhawa PK, Singh N, Jaggi AS (2016a) Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection. Naunyn Schmiedeberg’s Arch Pharmacol 389:1–9

    Article  CAS  Google Scholar 

  • Sharma R, Randhawa PK, Singh N, Jaggi AS (2016b) Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection. Naunyn Schmiedeberg’s Arch Pharmacol 389(1):1–9

    Article  CAS  Google Scholar 

  • Shintani Y, Node K, Asanuma H, Sanada S, Takashima S, Asano Y, Liao Y, Fujita M, Hirata A, Shinozaki Y, Fukushima T, Nagamachi Y, Okuda H, Kim J, Tomoike H, Hori M, Kitakaze M (2004) Opening of Ca2+-activated K+ channels is involved in ischemic preconditioning in canine hearts. J Mol Cell Cardiol 37:1213–1218

    CAS  PubMed  Google Scholar 

  • Singh B, Randhawa PK, Singh N, Jaggi AS (2016) Investigations on the role of leukotrienes in remote hind limb preconditioning-induced cardioprotection in rats. Life Sci 152:238–243

    Article  CAS  PubMed  Google Scholar 

  • Vivaldi MT, Kloner RA, Schoen FJ (1985) Triphenyltetrazolium staining of irreversible ischemic injury following coronary artery occlusion in rats.Am J Pathol 121(3):522–30

  • Vriens J, Appendino G, Nilius B (2009) Pharmacology of vanilloid transient receptor potential cation channels. Mol Pharmacol 75:1262–1279

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Wang DH (2005) TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 112:3617–3623

    Article  CAS  PubMed  Google Scholar 

  • Wei Z, Wang L, Han J, Song J, Yao L, Shao L, Sun Z, Zheng L (2009) Decreased expression of transient receptor potential vanilloid 1 impairs the postischemic recovery of diabetic mouse hearts. Circ J 73:1127–1132

    Article  CAS  PubMed  Google Scholar 

  • Wever KE, Warlé MC, Wagener FA, van der Hoorn JW, Masereeuw R, van der Vliet JA, Rongen GA (2011) Remote ischaemic preconditioning by brief hind limb ischaemia protects against renal ischaemia-reperfusion injury: the role of adenosine. Nephrol Dial Transplant 26:3108–3117

    Article  CAS  PubMed  Google Scholar 

  • White SK, Frohlich GM, Sado DM, Maestrini V, Fontana M, Treibel TA, Tehrani S, Flett AS, Meier P, Ariti C, Davies JR, Moon JC, Yellon DM, Hausenloy DJ (2015) Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv (1 Pt B):178–188

  • Yang D, Luo Z, Ma S, Wong WT, Ma L, Zhong J, He H, Zhao Z, Cao T, Yan Z, Liu D, Arendshorst WJ, Huang Y, Tepel M, Zhu Z (2010) Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 12(2):130–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao X, Li Y, Tao M, Wang S, Zhang L, Lin J, Xia Z, Liu HM (2015) Effects of glucose concentration on propofol cardioprotection against myocardial ischemia reperfusion injury in isolated rat hearts. J Diabetes Res 2015:592028

    Article  PubMed  PubMed Central  Google Scholar 

  • Zahner MR, Li DP, Chen SR, Pan HL (2003) Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J Physiol 551:515–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng LR, Zhang YY, Han J, Sun ZW, Zhou SX, Zhao WT, Wang LH (2015) Nerve growth factor rescues diabetic mice heart after ischemia/reperfusion injury via up-regulation of the TRPV1 receptor. J Diabetes Complicat 29:323–328

    Article  PubMed  Google Scholar 

  • Zhong B, Wang DH (2009) Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors. Am J Physiol Regul Integr Comp Physiol 297:R1681–R1690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

The authors are thankful to the Department of Science and Technology F. No. SB/SO/HS/0004/2013, New Delhi, for providing us financial assistance and the Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India, for supporting us.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India

    Puneet Kaur Randhawa & Amteshwar Singh Jaggi

Authors
  1. Puneet Kaur Randhawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amteshwar Singh Jaggi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amteshwar Singh Jaggi.

Ethics declarations

The experimental protocol was approved by the Institutional Animal Ethics Committee, and care of the animals was carried out as per the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forest, Government of India (Reg. No. 107/99/CPCSEA/2013-37).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Randhawa, P.K., Jaggi, A.S. Investigating the involvement of TRPV1 ion channels in remote hind limb preconditioning-induced cardioprotection in rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 117–126 (2017). https://doi.org/10.1007/s00210-016-1311-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1311-x

Keywords

Search

Navigation