Abstract
Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff’s system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, −dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, −dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg−1) and ruthenium red (4 and 8 mg kg−1) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels.
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References
Ali N, Rizwi F, Iqbal A, Rashid A (2010) Induced remote ischemic pre-conditioning on ischemia-reperfusion injury in patients undergoing coronary artery bypass. J Coll Physicians Surg Pak 20:427–431
Babiker FA, Lorenzen-Schmidt I, Mokelke E, Vanagt WY, Delhaas T, Waltenberger J, Cleutjens JP, Prinzen FW (2010) Long-term protection and mechanism of pacing-induced postconditioning in the heart. Basic Res Cardiol 105:523–533
Bett GC, Sachs F (1997) Cardiac mechanosensitivity and stretch-activated ion channels. Trends Cardiovasc Med 7:4–8
Biagi BA, Enyeart JJ (1990) Gadolinium blocks low- and high-threshold calcium currents in pituitary cells. Am J Phys 259:C515–C520
Bickler PE, Fahlman CS (2010) Enhanced hypoxic preconditioning by isoflurane: signaling gene expression and requirement of intracellular Ca2+ and inositol triphosphate receptors. Brain Res 1340:86–95
Chen M, Zheng YY, Song YT, Xue JY, Liang ZY, Yan XX, Luo DL (2016) Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats. Acta Pharmacol Sin 37(4):453–462
Choi HJ, Sun D, Jakobs TC (2015) Astrocytes in the optic nerve head express putative mechanosensitive channels. Mol Vis 21:749–766
Craelius W, Chen V, el-Sherif N (1988) Stretch activated ion channels in ventricular myocytes. Biosci Rep 8:407–414
Davis MJ, Donovitz JA, Hood JD (1992) Stretch-activated single-channel and whole cell currents in vascular smooth muscle cells. Am J Phys 262:C1083–C1088
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
Du SS, Qiang M, Zeng ZC, Ke AW, Ji Y, Zhang ZY, Zeng HY, Liu Z (2010) Inactivation of kupffer cells by gadolinium chloride protects murine liver from radiation-induced apoptosis. Int J Radiat Oncol Biol Phys 76:1225–1234
Fischer MJ, Reeh PW, Sauer SK (2003) Proton-induced calcitonin gene-related peptide release from rat sciatic nerve axons, in vitro, involving TRPV1. Eur J Neurosci 18:803–810
Friedrich O, Wagner S, Battle AR, Schürmann S, Martinac B (2012) Mechano-regulation of the beating heart at the cellular level-mechanosensitive channels in normal and diseased heart. Prog Biophys Mol Biol 110:226–238
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
Guibert C, Ducret T, Savineau JP (2008) Voltage-independent calcium influx in smooth muscle. Prog Biophys Mol Biol 98:10–23
Guzy PM (1977) Creatine phosphokinase-MB (CPK-MB) and the diagnosis of myocardial infarction. West J Med 127:455–460
Gysembergh A, Margonari H, Loufoua J, Ovize A, André-Fouët X, Minaire Y, Ovize M (1998) Stretch-induced protection shares a common mechanism with ischemic preconditioning in rabbit heart. Am J Phys 274:H955–H964
Hamill OP, Martinac B (2001) Molecular basis of mechanotransduction in living cells. Physiol Rev 81:685–740
Hamlin RL, del Rio C (2012) dP/dt(max)—a measure of ‘baroinometry’. J Pharmacol Toxicol Methods 66:63–65
Hao J, Kim HS, Choi W, Ha TS, Ahn HY, Kim CH (2010) Mechanical stretch-induced protection against myocardial ischemia-reperfusion injury involves AMP-activated protein kinase. Korean J Physiol Pharmacol 14:1–9
Haswell ES, Phillips R, Rees DC (2011) Mechanosensitive channels: what can they do and how do they do it? Structure 19:1356–1369
Hayabuchi Y, Nakaya Y, Mawatari K, Inoue M, Sakata M, Kagami S (2011) Cell membrane stretch activates intermediate-conductance Ca2+-activated K+ channels in arterial smooth muscle cells. Heart Vessel 26:91–100
Hu J, Lewin GR (2006) Mechanosensitive currents in the neurites of cultured mouse sensory neurones. J Physiol 577:815–828
Huang CH, Wang JS, Chiang SC, Wang YY, Lai ST, Weng ZC (2004) Brief pressure overload of the left ventricle preconditions rabbit myocardium against infarction. Ann Thorac Surg 78:628–633
Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229–317
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
Kemp M, Donovan J, Higham H, Hooper J (2004) Biochemical markers of myocardial injury. Br J Anaesth 93:63–73
Kerstein PC, Jacques-Fricke BT, Rengifo J, Mogen BJ, Williams JC, Gottlieb PA, Sachs F, Gomez TM (2013) Mechanosensitive TRPC1 channels promote calpain proteolysis of talin to regulate spinal axon outgrowth. J Neurosci 33:273–285
Kim D (1992) A mechanosensitive K+ channel in heart cells. Activation by arachidonic acid. J Gen Physiol 100:1021–1040
King JA (1959) A routine method for estimation of lactate dehydrogenase activity. J Med Lab Tech 16:291–332
Kyriakou LG, Tzirogiannis KN, Demonakou MD, Kourentzi KT, Mykoniatis MG, Panoutsopoulos GI (2013) Gadolinium chloride pretreatment ameliorates acute cadmium-induced hepatotoxicity. Toxicol Ind Health 29:624–632
Langendorff O (1885) Untersuchungen amuber lebenderer saugethierherzen. Pfluger Arch Gesmate Physio 61:291–332
Lansman JB, Franco-Obregón A (2006) Mechanosensitive ion channels in skeletal muscle: a link in the membrane pathology of muscular dystrophy. Clin Exp Pharmacol Physiol 33:649–656
Lehoux S, Tedgui A (2003) Cellular mechanics and gene expression in blood vessels. J Biomech 36:631–643
Levine JD, Alessandri-Haber N (2007) TRP channels: targets for the relief of pain. Biochim Biophys Acta 1772:989–1003
Liang N, Wang P, Wang S, Li S, Li Y, Wang J, Wang M (2014) Role of mitochondrial calcium uniporter in regulating mitochondrial fission in the cerebral cortexes of living rats. J Neural Transm (Vienna) 121:593–600
Lotteau S, Ducreux S, Romestaing C, Legrand C, Van Coppenolle F (2013) Characterization of functional TRPV1 channels in the sarcoplasmic reticulum of mouse skeletal muscle. PLoS ONE 8:e58673
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
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 (2012) TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice. Cell Res 22:551–564
Nakagawa C, Asayama J, Katamura M, Matoba S, Keira N, Kawahara A, Tsuruyama K, Tanaka T, Kobara M, Akashi K, Ohta B, Tatsumi T, Nakagawa M (1997) Myocardial stretch induced by increased left ventricular diastolic pressure preconditions isolated perfused hearts of normotensive and spontaneously hypertensive rats. Basic Res Cardiol 92:410–416
Nilius B, Viana F, Droogmans G (1997) Ion channels in vascular endothelium. Annu Rev Physiol 59:145–170
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
Obadia JF, Ovize M, Maupoil V, Terrand J, Abadie C, Ovize A, Andre-Fouët X, Minaire Y, Rochette L (1997) Beneficial actions of preconditioning and stretch on postischemic contractile function of isolated working rat heart: effects of staurosporine. J Cardiovasc Pharmacol 30:191–196
Ortiz GG, de la Mora-Rivas G, Cardenas-Ortega A, Orbach-Arbouys S, Bravo-Cuellar A, Feria-Velasco A (1992) Hepatotoxicity induced by a single ip injection of ruthenium red. Biomed Pharmacother 46:115–119
Ovize M, Kloner RA, Przyklenk K (1994) Stretch preconditions canine myocardium. Am J Phys 266:H137–H146
Parra VM, Macho P, Sánchez G, Donoso P, Domenech RJ (2015) Exercise preconditioning of myocardial infarct size in dogs is triggered by calcium. J Cardiovasc Pharmacol 65:276–281
Perretti F, Manzini S (1993) Activation of capsaicin-sensitive sensory fibers modulates PAF-induced bronchial hyperresponsiveness in anesthetized guinea pigs. Am Rev Respir Dis 148(4 Pt 1):927–931
Przyklenk K, Hata K, Kloner RA (1997) Is calcium a mediator of infarct size reduction with preconditioning in canine myocardium? Circulation 96:1305–1312
Przyklenk K, Whittaker P (2013) Genesis of remote conditioning: action at a distance--‘hypotheses non fingo’? J Cardiovasc Med (Hagerstown) 14(3):180–186
Randhawa PK, Jaggi AS (2015) TRPV4 channels: physiological and pathological role in cardiovascular system. Basic Res Cardiol 110:54
Randhawa PK, Bali A, Jaggi AS (2015) RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms. Eur J Pharmacol 746:317–332
Rath G, Saliez J, Behets G, Romero-Perez M, Leon-Gomez E, Bouzin C, Vriens J, Nilius B, Feron O, Dessy C (2012) Vascular hypoxic preconditioning relies on TRPV4-dependent calcium influx and proper intercellular gap junctions communication. Arterioscler Thromb Vasc Biol 32:2241–2249
Rehni AK, Singh N, Jaggi AS (2007) Possible involvement of insulin, endogenous opioids and calcitonin gene-related peptide in remote ischaemic preconditioning of the brain. Yakugaku Zasshi 127:1013–1020
Ren JY, Song JX, Lu MY, Chen H (2011) 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 169:49–57
Schultz HD (2003) The spice of life is at the root of cardiac pain. J Physiol 551(Pt 2):400
Senatore A, Monteil A, van Minnen J, Smit AB, Spafford JD (2013) NALCN ion channels have alternative selectivity filters resembling calcium channels or sodium channels. PLoS ONE 8:e55088
Shenton FC, Pyner S (2014) Expression of transient receptor potential channels TRPC1 and TRPV4 in venoatrial endocardium of the rat heart. Neuroscience 267:195–204
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
Spencer AJ, Wilson SA, Batchelor J, Reid A, Rees J, Harpur E (1997) Gadolinium chloride toxicity in the rat. Toxicol Pathol 25:245–255
Spicarova D, Nerandzic V, Palecek J (2014) Update on the role of spinal cord TRPV1 receptors in pain modulation. Physiol Res 63(Suppl 1):S225–S236
Su X, Wachtel RE, Gebhart GF (2000) Mechanosensitive potassium channels in rat colon sensory neurons. J Neurophysiol 84:836–843
Vivaldi MT, Kloner RA, Schoen FJ (1985) Triphenyltetrazolium staining of irreversible ischemic injury following coronary artery occlusion in rats. Am J Pathol 121:522–530
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 ischaemiareperfusion injury: the role of adenosine. Nephrol Dial Transplant 26:3108–3117
Xian Tao L, Dyachenko V, Zuzarte M, Putzke C, Preisig-Müller R, Isenberg G, Daut J (2006) The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle. Cardiovasc Res 69:86–97
Yao X, Kwan HY, Dora KA, Garland CJ, Huang Y (2003) A mechanosensitive cation channel in endothelial cells and its role in vasoregulation. Biorheology 40:23–30
Zhang Y, Liu X, Yan F, Min L, Ji X, Luo Y (2012) Protective effects of remote ischemic preconditioning in rat hindlimb onischemia- reperfusion injury. Neural Regen Res 7:583–587
Zheng J (2013) Molecular mechanism of TRP channels. Compr Physiol 3:221–242
Zhong B, Wang DH (2007) TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol 293:H1791–H1798
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The authors are thankful to Department of Science and Technology F. No. SB/SO/HS/0004/2013, New Delhi, for their gratefulness for providing us financial assistance and Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting us.
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Randhawa, P.K., Jaggi, A.S. 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, 887–896 (2016). https://doi.org/10.1007/s00210-016-1251-5
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DOI: https://doi.org/10.1007/s00210-016-1251-5