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B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart

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Abstract

Natriuretic peptides are regulatory autacoids in the mammalian myocardium whose functions, mediated via particulate guanylyl cyclase/cGMP, may include cytoprotection against ischaemia-reperfusion injury. Previous work has identified that B-type natriuretic peptide (BNP) limits infarct size when administered prior to and during coronary occlusion through a KATP channel-dependent mechanism. The present study examined the hypothesis that the protection afforded by BNP is mediated specifically at reperfusion in a postconditioning-like manner. Langendorff-perfused rat hearts were subjected to 35 min coronary artery occlusion and 120 min reperfusion, and infarct size was determined by tetrazolium staining. Postconditioning was effected by applying six 10-second periods of global ischaemia at the onset of reperfusion.Treatment with either BNP 10 nM or the NO donor S-nitroso-N-acetylpenicillamine (SNAP) 1–10 μM was commenced 5 min prior to reperfusion and continued until 10 min after reperfusion. Control infarct size (% of ischaemic risk zone) was 40.8 ± 3.7%.BNP at reperfusion induced a significant limitation of infarct size (BNP 22.9 ± 4.1% P<0.05 vs. control). Co-treatment at reperfusion with BNP and the KATP channel blockers 5-hydroxydecanote (5HD, 100 μM), glibenclamide (Glib; 10 μM) or HMR1098 (10 μM) abolished the infarct-limiting effect of BNP (BNP + 5HD 41.0 ± 3.9%, BNP + Glib 39.8 ± 5.6%, BNP + HMR 1098 46.0 ± 7.1%,P < 0.05 vs. BNP). BNP given together with L-NAME (100 μM) at reperfusion resulted in a marked loss of protection (BNP + L-NAME 53.1 ± 3.8% P < 0.001 vs. BNP). In a second series of experiments, SNAP (1–10 μM) given at reperfusion was found not to be protective (SNAP 1 μM 30.2 ± 4.9%, SNAP 2 μM 27.5 ± 9.5%, SNAP 5 μM 39.2 ± 5.7%, SNAP 10 μM 33.7 ± 6.4%, not significant vs. control). In a third series of experiments, postconditioning significantly limited infarct size (14.9 ± 3.6 % vs. control 34.5 ± 4.9%, P < 0.01) and this effect of postconditioning was abolished in the presence of isatin (100 μM), a non-specific blocker of particulate guanylyl cyclases (35.1 ± 6%, P < 0.05 vs. postconditioning). In conclusion, pharmacological activation of pGC by BNP can effectively induce protection against reperfusion injury, by mechanisms involving KATP channel opening and endogenous NO synthase activation. Furthermore, endogenous activation of pGC could play a role in the mechanism of postconditioning.

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Abbreviations

ANP:

atrial natriuretic peptide

BNP:

B-type natriuretic peptide

CAO:

coronary artery occlusion

cGMP:

cyclic guanosine 3’5’monophosphate

CNP:

C-type natriuretic peptide

DMSO:

dimethylsulfoxide

Glib:

glibenclamide

5HD:

5-hydroxydecanote

KATP :

ATP-sensitive potassium channel

L-NAME:

Nω-Nitro-L-arginine methyl ester

NO:

nitric oxide

NOS:

nitric oxide synthase

NPR:

natriuretic peptide receptor

NPs:

natriuretic peptides

pGC:

particulate guanylyl cyclase

PKG:

cGMP-dependent protein kinase

sGC:

soluble guanylyl cyclase

SNAP:

S-nitroso-N-acetylpenicillamine

References

  1. Abdallah Y, Gkatzoflia A, Pieper H, Zoga E, Walther S, Kasseckert S, Schafer M, Schluter KD, Piper HM, Schafer C (2005) Mechanism of cGMP-mediated protection in a cellular model of myocardial reperfusion injury. Cardiovasc Res 66:123–131

    Article  PubMed  CAS  Google Scholar 

  2. Agullo L, Garcia-Dorado D, Escalona N, Ruiz-Meana M, Inserte J, Soler-Soler J (2003) Effect of ischemia on soluble and particulate guanylyl cyclase-mediated cGMP synthesis in cardiomyocytes. Am J Physiol Heart Circ Physiol 284:H2170–H2176

    PubMed  CAS  Google Scholar 

  3. Agullo L, Garcia-Dorado D, Escalona N, Ruiz-Meana M, Mirabet M, Inserte J, Soler-Soler J (2005) Membrane association of nitric oxide-sensitive guanylyl cyclase in cardiomyocytes. Cardiovasc Res 68:65–74

    Article  PubMed  CAS  Google Scholar 

  4. Anand-Srivastava MB (2005) Natriuretic peptide receptor-C signaling and regulation. Peptides 26:1044–1059

    Article  PubMed  CAS  Google Scholar 

  5. Baczko I, Jones L, McGuigan CF, Manning Fox JE, Gandhi M, Giles WR, Clanachan AS, Light PE (2005) Plasma membrane KATP channel-mediated cardioprotection involves posthypoxic reductions in calcium overload and contractile dysfunction: mechanistic insights into cardioplegia. FASEB J 19:980–982

    PubMed  CAS  Google Scholar 

  6. Bell RM, Maddock HL, Yellon DM (2003) The cardioprotective and mitochondrial depolarising properties of exogenous nitric oxide in mouse heart. Cardiovasc Res 57:405–415

    Article  PubMed  CAS  Google Scholar 

  7. Bolli R (2001) Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol 33:1897–1918

    Article  PubMed  CAS  Google Scholar 

  8. Burkhardt M, Glazova M, Gambaryan S, Vollkommer T, Butt E, Bader B, Heermeier K, Lincoln TM, Walter U, Palmetshofer A (2000) KT5823 inhibits cGMPdependent protein kinase activity in vitro but not in intact human platelets and rat mesangial cells. J Biol Chem 275:33536–33541

    Article  PubMed  CAS  Google Scholar 

  9. Burley DS, Baxter GF (2005) Post-conditioning is dependent on PKG activation in early reperfusion. J Mol Cell Cardiol 38:1008–1009 (abstract)

    Google Scholar 

  10. Burley DS, Ferdinandy P, Baxter GF (2007) Cyclic GMP and protein kinase- G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signalling. Br J Pharmacol (in press)

  11. Costa AD, Garlid KD,West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD (2005) Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 97:329–336

    Article  PubMed  CAS  Google Scholar 

  12. D’Souza SP, Davis M, Baxter GF (2004) Autocrine and paracrine actions of natriuretic peptides in the heart. Pharmacol Ther 101:113–129

    Article  PubMed  CAS  Google Scholar 

  13. D’Souza SP, Yellon DM, Martin C, Schulz R, Heusch G, Onody A, Ferdinandy P, Baxter GF (2003) B-type natriuretic peptide limits infarct size in rat isolated hearts via KATP channel opening. Am J Physiol Heart Circ Physiol 284:H1592–H1600

    PubMed  Google Scholar 

  14. du Toit EF, Rossouw E, Salie R, Opie LH, Lochner A (2005) Effect of sildenafil on reperfusion function, infarct size, and cyclic nucleotide levels in the isolated rat heart model. Cardiovasc Drugs Ther 19:23–31

    Article  PubMed  CAS  Google Scholar 

  15. Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F (2003) Cyclic GMPdependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res 93:907–916

    Article  PubMed  CAS  Google Scholar 

  16. Giustarini D, Milzani A, Colombo R, Dalle-Donne I, Rossi R (2003) Nitric oxide and S-nitrosothiols in human blood. Clin Chim Acta 330:85–98

    Article  PubMed  CAS  Google Scholar 

  17. Gross GJ, Peart JN (2003) KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol 285:H921–H930

    PubMed  CAS  Google Scholar 

  18. Hart CY, Hahn EL, Meyer DM, Burnett JC Jr, Redfield MM (2001) Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs. Am J Physiol Heart Circ Physiol 281:H146–H154

    PubMed  CAS  Google Scholar 

  19. Hausenloy DJ, Tsang A, Yellon DM (2005) The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 15:69–75

    Article  PubMed  CAS  Google Scholar 

  20. Hempel A, Friedrich M, Schluter KD, Forssmann WG, Kuhn M, Piper HM (1997) ANP protects against reoxygenation- induced hypercontracture in adult cardiomyocytes. Am J Physiol Heart Circ Physiol 273:H244–H249

    CAS  Google Scholar 

  21. Hobbs A, Foster P, Prescott C, Scotland R, Ahluwalia A (2004) Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide. Circulation 110:1231–1235

    Article  PubMed  CAS  Google Scholar 

  22. Huang J, Mahavadi S, Sriwai W, Hu W, Murthy KS (2006) Gi-coupled receptors mediate phosphorylation of CPI-17 and MLC20 via preferential activation of the PI3K/ILK pathway. Biochem J 396:193–200

    Article  PubMed  CAS  Google Scholar 

  23. Inserte J, Garcia-Dorado D, Agullo L, Paniagua A, Soler-Soler J (2000) Urodilatin limits acute reperfusion injury in the isolated rat heart. Cardiovasc Res 45:351–359

    Article  PubMed  CAS  Google Scholar 

  24. Krolikowski JG, Bienengraeber M, Weihrauch D, Warltier DC, Kersten JR, Pagel PS (2005) Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion: the role of mitochondrial KATP channels. Anesth Analg 101:1590–1596

    Article  PubMed  CAS  Google Scholar 

  25. Kwan HY, Huang Y,Yao X (2000) Storeoperated calcium entry in vascular endothelial cells is inhibited by cGMP via a protein kinase G-dependent mechanism. J Biol Chem 275:6758–6763

    Article  PubMed  CAS  Google Scholar 

  26. Lincoln TM, Dey N, Sellak H (2001) cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression. J Appl Physiol 91:1421–1430

    PubMed  CAS  Google Scholar 

  27. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52:375–414

    PubMed  CAS  Google Scholar 

  28. Matheus ME, Violante FD, Garden SJ, Pinto AC, Fernandes PD (2006) Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line. Eur J Pharmacol 556:200–206

    Article  PubMed  CAS  Google Scholar 

  29. Medvedev A, Crumeyrolle-Arias M, Cardona A, Sandler M, Glover V (2005) Natriuretic peptide interaction with [3H]isatin binding sites in rat brain. Brain Res 1042:119–124

    Article  PubMed  CAS  Google Scholar 

  30. Medvedev A, Sandler M, Glover V (1999) The influence of isatin on guanylyl cyclase of rat heart membranes. Eur J Pharmacol 384:239–241

    Article  PubMed  CAS  Google Scholar 

  31. Medvedev AE, Clow A, Sandler M, Glover V (1996) Isatin: a link between natriuretic peptides and monoamines? Biochem Pharmacol 52:385–391

    Article  PubMed  CAS  Google Scholar 

  32. Medvedev AE, Goodwin B, Clow A, Halket J, Glover V, Sandler M (1992) Inhibitory potency of some isatin analogues on human monoamine oxidase A and B. Biochem Pharmacol 44:590–592

    Article  PubMed  CAS  Google Scholar 

  33. Medvedev AE, Goodwin BL, Sandler M, Glover V (1999) Efficacy of isatin analogues as antagonists of rat brain and heart atrial natriuretic peptide receptors coupled to particulate guanylyl cyclase. Biochem Pharmacol 57:913–915

    Article  PubMed  CAS  Google Scholar 

  34. Medvedev AE, Sandler M, Glover V (1998) Interaction of isatin with type-A natriuretic peptide receptor: possible mechanism. Life Sci 62:2391–2398

    Article  PubMed  CAS  Google Scholar 

  35. Nishikimi T, Maeda N, Matsuoka H (2006) The role of natriuretic peptides in cardioprotection. Cardiovasc Res 69:318–328

    Article  PubMed  CAS  Google Scholar 

  36. Okawa H, Horimoto H, Mieno S, Nomura Y, Yoshida M, Shinjiro S (2003) Preischemic infusion of alpha-human atrial natriuretic peptide elicits myoprotective effects against ischemia reperfusion in isolated rat hearts. Mol Cell Biochem 248:171–177

    Article  PubMed  CAS  Google Scholar 

  37. Padilla F, Garcia-Dorado D, Agullo L, Barrabes JA, Inserte J, Escalona N, Meyer M, Mirabet M, Pina P, Soler-Soler J (2001) Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs. Cardiovasc Res 51:592–600

    Article  PubMed  CAS  Google Scholar 

  38. Piggott LA, Hassell KA, Berkova Z, Morris AP, Silberbach M, Rich TC (2006) Natriuretic peptides and nitric oxide stimulate cGMP synthesis in different cellular compartments. J Gen Physiol 128:3–14

    Article  PubMed  CAS  Google Scholar 

  39. Piper HM, Abdallah Y, Schafer C (2004) The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res 61:365–371

    Article  PubMed  Google Scholar 

  40. Potter LR, Abbey-Hosch S, Dickey DM (2006) Natriuretic peptides, their receptors, and cyclic guanosine monophosphate- dependent signaling functions. Endocr Rev 27:47–72

    Article  PubMed  CAS  Google Scholar 

  41. Qin Q,Yang XM, Cui L, Critz SD, Cohen MV, Browner NC, Lincoln TM, Downey JM (2004) Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism. Am J Physiol Heart Circ Physiol 287:H712–H718

    Article  PubMed  CAS  Google Scholar 

  42. Ren B, Shen Y, Shao H, Qian J, Wu H, Jing H (2007) Brain natriuretic peptide limits myocardial infarct size dependent of nitric oxide synthase in rats. Clin Chim Acta 377:83–87

    Article  PubMed  CAS  Google Scholar 

  43. Schulz R, Kelm M, Heusch G (2004) Nitric oxide in myocardial ischemia/ reperfusion injury. Cardiovasc Res 61:402–413

    Article  PubMed  CAS  Google Scholar 

  44. Scotland RS, Cohen M, Foster P, Lovell M, Mathur A, Ahluwalia A, Hobbs AJ (2005) C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. Proc Natl Acad Sci USA 102:14452–14457

    Article  PubMed  CAS  Google Scholar 

  45. Su J, Scholz PM, Weiss HR (2005) Differential effects of cGMP produced by soluble and particulate guanylyl cyclase on mouse ventricular myocytes. Exp Biol Med 230:242–250

    CAS  Google Scholar 

  46. Takagi G, Kiuchi K, Endo T, Yamamoto T, Sato N, Nejima J, Takano T (2000) Alpha- human atrial natriuretic peptide, carperitide, reduces infarct size but not arrhythmias after coronary occlusion/ reperfusion in dogs. J Cardiovasc Pharmacol 36:22–30

    Article  PubMed  CAS  Google Scholar 

  47. Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM (2004) Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95:230–232

    Article  PubMed  CAS  Google Scholar 

  48. Tsang A, Hausenloy DJ, Yellon DM (2005) Myocardial postconditioning: reperfusion injury revisited. Am J Physiol Heart Circ Physiol 289:H2–H7

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Gary F. Baxter PhD, FIBiol, FESC, FAHA.

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Burley, D.S., Baxter, G.F. B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. Basic Res Cardiol 102, 529–541 (2007). https://doi.org/10.1007/s00395-007-0672-1

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  • DOI: https://doi.org/10.1007/s00395-007-0672-1

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