Abstract
The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff’s isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.
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References
Randhawa PK, Bali A, Jaggi AS. RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms. Eur J Pharmacol. 2015;746:317–32.
Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic' preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87:893–9.
Kharbanda RK, Mortensen UM, White PA. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106:2881.
Diwan V, Kant R, Jaggi AS, Singh N, Singh D. Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem. 2008;315:195–201.
Singh B, Randhawa PK, Singh N, Jaggi AS. Investigations on the role of leukotrienes in remote hind limb preconditioning-induced cardioprotection in rats. Life Sci. 2016;152:238–3.
Wang Y, Kudo M, Xu M, Ayub A, Ashraf M. Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. J Mol Cell Cardiol. 2001;33(11):2037–6.
Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans. J Am Coll Cardiol. 2005;46:450–6.
Candilio L, Malik A, Ariti C, Khan SA, Barnard M, Di Salvo C, et al. A retrospective analysis of myocardial preservation techniques during coronary artery bypass graft surgery: are we protecting the heart? J Cardiothorac Surg. 2014;9:184.
Ali N, Rizwi F, Iqbal A, Rashid A. Induced remote ischemic pre-conditioning on ischemia-reperfusion injury in patients undergoing coronary artery bypass. J Coll Physicians Surg Pak. 2010;20:427–1.
Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, et al. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med. 2015;373:1397–07.
Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015;373:1408–17.
Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol- a clinical trial. Acta Anaesthesiol Scand. 2012;56:30–8.
Hasko G, Cronstein BN. Adenosine: an endogenous regulator of innate immunity. Trends Immunol. 2004;25:33–9.
Lynge J, Hellsten Y. Distribution of adenosine A1, A2A and A2B receptors in human skeletal muscle. Acta Physiol Scand. 2000;169(4):283–90.
Tian Y, Piras BA, Kron IL, French BA, Yang Z. Adenosine 2B receptor activation reduces myocardial reperfusion injury by promoting anti-inflammatory macrophages differentiation via PI3K/Akt pathway. Oxidative Med Cell Longev. 2015;2015:585297.
Mustafa SJ, Morrison RR, Teng B, Pelleg A. Adenosine receptors and the heart: role inregulation of coronary blood flow and cardiac electrophysiology. Handb Exp Pharmacol. 2009;193:161–88.
Lankford AR, Yang JN, Rose'Meyer R, French BA, Matherne GP, Fredholm BB, Yang Z. Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2006;290:H1469–3.
Dong JH, Liu YX, Ji ES, He RR. Limb ischemic preconditioning reduces infarct size following myocardial ischemia-reperfusion in rats. Sheng Li Xue Bao. 2004;56:41–6.
Hu S, Dong H, Zhang H, Wang S, Hou L, Chen S, Zhang J, Xiong L. Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats. Brain Res. 2012;1459:81–90.
Wang L, Wang DH. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation. 2005;112(23):3617–23.
Nilius B, Owsianik G, Voets T, Peters JA. Transient receptor potential cation channels in disease. Physiol Rev. 2007;87:165–217.
Zhong B, Wang DH. TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol. 2007;293:H1791–8.
Hao J, Kim HS, Choi W, Ha TS, Ahn HY, Kim CH. Mechanical stretch-induced protection against myocardial ischemia-reperfusion injury involves AMP-activated protein kinase. Korean J Physiol Pharmacol. 2010;14:1–9.
Gysembergh A, Margonari H, Loufoua J, Ovize A, André-Fouët X, Minaire Y, Ovize M. Stretch-induced protection shares a common mechanism with ischemic preconditioning in rabbit heart. Am J Phys. 1998;274:H955–64.
Perretti F, Manzini S. Activation of capsaicin-sensitive sensory fibers modulates PAF-induced bronchial hyperresponsiveness in anesthetized Guinea pigs. Am Rev Respir Dis. 1993;148:927–1.
Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298(5871):240–4.
Franco-Cereceda A, Kfillner G, Lundberg JM. Cyclooxygenase products released by low pH have capsaicin-like actions on sensory nerves in the isolated Guinea pig heart. Cardiovasc Res. 1994;28:365.
Franco-Cereceda A. Calcitonin gene-related peptide and tachykinins in relation to local sensory control of cardiac contractility and coronary vascular tone. Acta Physiol Scand. 1988;133:3.
D'Alonzo AJ, Grover GJ, Darbenzio RB, Hess TA, Sleph PG, Dzwonczyk S, Zhu JL, Sewter JC. In vitro effects of capsaicin: antiarrhythmic and antiischemic activity. Eur J Pharmcol. 1995;272:269–78.
Lu MJ, Chen YS, Huang HS, Ma MC. Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway. Basic Res Cardiol. 2014;109:414.
Eltrop CT, Jansen-Olesen I, Hansen AJ. Release of calcitonin gene-related peptide (CGRP) from Guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide. Cephalagia. 2000;20(9):838–44.
Forouzannia SK, Abdollahi MH, Mirhosseini SJ, Hadadzadeh M, Zarepur R, Zarepur E, Beiki O, Sarebanhassanabadi M. Adenosine preconditioning versus ischemic preconditioning in patients undergoing off-pump coronary artery bypass (OPCAB). J Tehran Heart Cent. 2013;8(3):127–31.
Randhawa PK, Jaggi AS. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. Naunyn Schmiedeberg's Arch Pharmacol. 2016;389(8):887–96.
Rehni AK, Singh TG, Jaggi AS, Singh N. Pharmacological preconditioning of the brain: a possible interplay between opioid and calcitonin gene related peptide transduction systems. Pharmacol Rep. 2008;60(6):904–13.
Ghelardini C, Galeotti N, Figini M, Imperato A, Nicolodi M, Sicuteri F, Gessa GL, Bartolini A. The central cholinergic system has a role in the antinociception induced in rodents and Guinea pigs by the antimigraine drug sumatriptan. J Pharmacol Exp Ther. 1996;279(2):884–90.
Sharma R, Randhawa PK, Singh N, Jaggi AS. Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection. Naunyn Schmiedeberg's Arch Pharmacol. 2016;389(1):1–9.
Randhawa PK, Jaggi AS. Investigating the involvement of TRPV1 ion channels in remote hind limb preconditioning-induced cardioprotection in rats. Naunyn Schmiedeberg's Arch Pharmacol. 2016;390:117–26.
Bell RM, Mocanu MM, Yellon DM. Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol. 2011;50:940–50.
Fishbein MC, Meerbaum S, Rit J, Lando U, Kanmatsuse K, Mercier JC, et al. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J. 1981;101:593–600.
King JA. A routine method for estimation of lactate dehydrogenase activity. J Med Lab Tech. 1959;16:291–32.
Kant R, Diwan V, Jaggi AS, Singh N, Singh D. Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases. Mol Cell Biochem. 2008;312:25–1.
Liem DA, Verdouw PD, Ploeg H, Kazim S, Duncker DJ. Sites of action of adenosine in interorgan preconditioning of the heart. Am J Physiol Heart Circ Physiol. 2002;283:H29–7.
Randhawa PK, Jaggi AS. Unraveling the role of adenosine in remote ischemic preconditioning-induced cardioprotection. Life Sci. 2016;155:140–6.
Pell TJ, Baxter GF, Yellon DM, Drew GM. Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels. Am J Phys. 1998;275:H1542–7.
Schultz HD. The spice of life is at the root of cardiac pain. J Physiol. 2003;551:400.
Fischer MJ, Reeh PW, Sauer SK. Proton-induced calcitonin gene-related peptide release from rat sciatic nerve axons, in vitro, involving TRPV1. Eur J Neurosci. 2003;18:803–10.
Lotteau S, Ducreux S, Romestaing C, Legrand C, Van Coppenolle F. Characterization of functional TRPV1 channels in the sarcoplasmic reticulum of mouse skeletal muscle. PLoS One. 2013;8:58673.
Luo Z, Ma L, Zhao Z, He H, Yang D, Feng X, Ma S, Chen X, Zhu T, Cao T, Liu D, Nilius B, Huang Y, Yan Z, Zhu Z. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice. Cell Res. 2012;22:551–64.
Xu L, Tripathy A, Pasek DA, Meissner G. Ruthenium red modifies the cardiac and skeletal muscle Ca(2+) release channels (ryanodine receptors) by multiple mechanisms. J Biol Chem. 1999;274(46):32680–91.
Friedrich O, Wagner S, Battle AR, Schürmann S, Martinac B. Mechano-regulation of the beating heart at the cellular level-mechanosensitive channels in normal and diseased heart. Prog Biophys Mol Biol. 2012;110:226–38.
Kim D. A mechanosensitive K+ channel in heart cells. Activation by arachidonic acid. J Gen Physiol. 1992;100:1021–40.
Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, Aoki KR, Lawrence GW, Dolly JO. Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci. 2009;29(15):4981–92.
Gao Y, Song J, Chen H, Cao C, Lee C. TRPV1 activation is involved in the cardioprotection of remote limb ischemic postconditioning in ischemia-reperfusion injury rats. Biochem Biophys Res Commun. 2015;463:1034–9.
Ren JY, Song JX, Lu MY, Chen H. Cardioprotection by ischemic postconditioning is lost in isolated perfused heart from diabetic rats: involvement of transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P. Regul Pept. 2011;169:49–57.
Wolfrum S, Nienstedt J, Heidbreder M, Schneider K, Dominiak P, Dendorfer A. Calcitonin gene related peptide mediates cardioprotection by remote preconditioning. Regul Pept. 2005;127(1–3):217–24.
Song S, Liu N, Liu W, Shi R, Guo KJ, Liu YF. The effect of pretreatment with calcitonin gene-related peptide on attenuation of liver ischemia and reperfusion injury due to oxygen free radicals and apoptosis. Hepato-Gastroenterology. 2009;56:1724–9.
Lei J, Zhu F, Zhang Y, Duan L, Lei H, Huang W. Transient receptor potential vanilloid subtype 1 inhibits inflammation and apoptosis via the release of calcitonin Gene-related peptide in the heart after myocardial infarction. Cardiology. 2016;134:436–43.
Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol. 2002;59(7):1084–8.
Longmore J, Razzaque Z, Shaw D, Davenport AP, Maguire J, Pickard JD, Schofield WN, Hill RG. Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors. Br J Clin Pharmacol. 1998;46(6):577–82.
Le Grand B, Vié B, John GW. Effects of sumatriptan on coronary flow and left ventricular function in the isolated perfused Guinea pig heart. J Cardiovasc Pharmacol. 1998;32(3):435–42.
Acknowledgements
The authors are grateful to the Department of Science and Technology (F. no. SB/SO/HS/0004/2013), New Delhi, for providing us financial assistance and Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting this study and providing technical facilities for the work.
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This study was funded by Department of Science and Technology F. No. SB/SO/HS/0004/2013, New Delhi, India
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Singh, A., Randhawa, P.K., Bali, A. et al. Exploring the Role of TRPV and CGRP in Adenosine Preconditioning and Remote Hind Limb Preconditioning-Induced Cardioprotection in Rats. Cardiovasc Drugs Ther 31, 133–143 (2017). https://doi.org/10.1007/s10557-017-6716-3
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DOI: https://doi.org/10.1007/s10557-017-6716-3