Skip to main content

Advertisement

SpringerLink
Log in

Candesartan Reduces the Hemorrhage Associated with Delayed Tissue Plasminogen Activator Treatment in Rat Embolic Stroke

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

We have previously reported that angiotensin receptor blockade reduces reperfusion hemorrhage in a suture occlusion model of stroke, despite increasing matrix metalloproteinase (MMP-9) activity. We hypothesized that candesartan will also decrease hemorrhage associated with delayed (6 h) tissue plasminogen activator (tPA) administration after embolic stroke, widening the therapeutic time window of tPA. Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) and treated with either candesartan (1 mg/kg) alone early at 3 h, delayed tPA (10 mg/kg) alone at 6 h, the combination of candesartan and tPA, or vehicle control. Rats were sacrificed at 24 and 48 h post-eMCAO and brains perfused for evaluation of neurological deficits, cerebral hemorrhage in terms of hemoglobin content, occurrence rate of hemorrhage, infarct size, tissue MMP activity and protein expression. The combination therapy of candesartan and tPA after eMCAO reduced the brain hemorrhage, and improved neurological outcome compared with rats treated with tPA alone. Further, candesartan in combination with tPA increased activity of MMP-9 but decreased MMP-3, nuclear factor kappa-B and tumor necrosis factor-α expression and enhanced activation of endothelial nitric oxide synthase. An activation of MMP-9 alone is insufficient to cause increased hemorrhage in embolic stroke. Combination therapy with acute candesartan plus tPA may be beneficial in ameliorating tPA-induced hemorrhage after embolic stroke.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

eMCAO:

Embolic middle cerebral artery occlusion

tPA:

Tissue plasminogen activator

PE:

Polyethylene

NF-κB:

Nuclear factor kappa-B

TNF-α:

Tumor necrosis factor-α

(p-eNOS):

Phospho endothelial nitric oxide synthase

MMP:

Matrix metalloproteinase

AT1R:

Angiotensin II type 1 receptor

Hb:

Hemoglobin

TTC:

2, 3, 5-triphenyltetrazolium chloride

SEM:

Standard error of the mean

CBF:

Cerebral blood flow

HT:

Hemorrhagic transformation

LRP:

Low-density lipoprotein receptor-related protein

BBB:

Blood brain-barrier

NO:

Nitric oxide

References

  1. Goldstein LB (2007) Acute ischemic stroke treatment in 2007. Circulation 116:1504–1514

    Article  PubMed  Google Scholar 

  2. Ishrat T, Soliman S, Guan W, Saler M, Fagan SC (2012) Vascular protection to increase the safety of tissue plasminogen activator for stroke. Curr Pharm Des 18:3677–3684

    Article  PubMed  CAS  Google Scholar 

  3. Fagan SC, Hess DC, Machado LS, Hohnadel EJ, Pollock DM, Ergul A (2005) Tactics for vascular protection after acute ischemic stroke. Pharmacotherapy 25:387–395

    Article  PubMed  Google Scholar 

  4. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jahnig P, Herrmann M, Knauth M, Bahr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C (2009) Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke J Cereb Circ 40:e647–e656

    Article  CAS  Google Scholar 

  5. Jia L, Chopp M, Zhang L, Lu M, Zhang Z (2010) Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke. Stroke J Cereb Circ 41:2071–2076

    Article  CAS  Google Scholar 

  6. Zechariah A, ElAli A, Hermann DM (2010) Combination of tissue-plasminogen activator with erythropoietin induces blood-brain barrier permeability, extracellular matrix disaggregation, and DNA fragmentation after focal cerebral ischemia in mice. Stroke J Cereb Circ 41:1008–1012

    Article  CAS  Google Scholar 

  7. Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, Lo EH (2003) Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9:1313–1317

    Article  PubMed  CAS  Google Scholar 

  8. Pfefferkorn T, Rosenberg GA (2003) Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke J Cereb Circ 34:2025–2030

    Article  Google Scholar 

  9. Montaner J, Alvarez-Sabin J, Molina C, Angles A, Abilleira S, Arenillas J, Gonzalez MA, Monasterio J (2001) Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke J Cereb Circ 32:1759–1766

    Article  CAS  Google Scholar 

  10. Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339

    Article  PubMed  Google Scholar 

  11. Romanic AM, Madri JA (1994) Extracellular matrix-degrading proteinases in the nervous system. Brain Pathol 4:145–156

    Article  PubMed  CAS  Google Scholar 

  12. Grossetete M, Rosenberg GA (2008) Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse. J cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 28:752–763

    Article  CAS  Google Scholar 

  13. Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, Yong VW, Peeling J (2003) Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 53:731–742

    Article  PubMed  CAS  Google Scholar 

  14. Wells JE, Biernaskie J, Szymanska A, Larsen PH, Yong VW, Corbett D (2005) Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice. Eur J Neurosci 21:187–196

    Article  PubMed  Google Scholar 

  15. Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M, Santamarina E, Quintana M, Monasterio J, Montaner J (2004) Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke J cerebral circulation 35:1316–1322

    Article  CAS  Google Scholar 

  16. Suzuki Y, Nagai N, Umemura K, Collen D, Lijnen HR (2007) Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J Thromb Haemost 5:1732–1739

    Article  PubMed  CAS  Google Scholar 

  17. Nishimura Y, Ito T, Saavedra JM (2000) Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke J Cereb Circ 31:2478–2486

    Article  CAS  Google Scholar 

  18. Awad AS (2011) Effect of combined treatment with curcumin and candesartan on ischemic brain damage in mice. J Stroke Cerebrovasc Dis 20:541–548

    Article  PubMed  Google Scholar 

  19. Fu H, Hosomi N, Pelisch N, Nakano D, Liu G, Ueno M, Miki T, Masugata H, Sueda Y, Itano T, Matsumoto M, Nishiyama A, Kohno M (2011) Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia. J Hypertens 29:2210–2219

    Article  PubMed  CAS  Google Scholar 

  20. Guan W, Kozak A, El-Remessy AB, Johnson MH, Pillai BA, Fagan SC (2011) Acute treatment with candesartan reduces early injury after permanent middle cerebral artery occlusion. Transl Stroke Res 2:179–185

    Article  PubMed  CAS  Google Scholar 

  21. Guan W, Somanath PR, Kozak A, Goc A, El-Remessy AB, Ergul A, Johnson MH, Alhusban A, Soliman S, Fagan SC (2011) Vascular protection by angiotensin receptor antagonism involves differential VEGF expression in both hemispheres after experimental stroke. PLoS ONE 6:e24551

    Article  PubMed  CAS  Google Scholar 

  22. Kozak A, Ergul A, El-Remessy AB, Johnson MH, Machado LS, Elewa HF, Abdelsaid M, Wiley DC, Fagan SC (2009) Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke. Stroke J Cereb Circ 40:1870–1876

    Article  CAS  Google Scholar 

  23. Elewa HF, Kozak A, Johnson MH, Ergul A, Fagan SC (2007) Blood pressure lowering after experimental cerebral ischemia provides neurovascular protection. J Hypertens 25:855–859

    Article  PubMed  CAS  Google Scholar 

  24. Fagan SC, Kozak A, Hill WD, Pollock DM, Xu L, Johnson MH, Ergul A, Hess DC (2006) Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection. J Hypertens 24:535–539

    Article  PubMed  CAS  Google Scholar 

  25. Zhang RL, Chopp M, Zhang ZG, Jiang Q, Ewing JR (1997) A rat model of focal embolic cerebral ischemia. Brain Res 766:83–92

    Article  PubMed  CAS  Google Scholar 

  26. Meng W, Wang X, Asahi M, Kano T, Asahi K, Ackerman RH, Lo EH (1999) Effects of tissue type plasminogen activator in embolic versus mechanical models of focal cerebral ischemia in rats. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 19:1316–1321

    Article  CAS  Google Scholar 

  27. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke J Cereb Circ 39:3372–3377

    Article  CAS  Google Scholar 

  28. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke J Cereb Circ 17:472–476

    Article  CAS  Google Scholar 

  29. Rosell A, Ortega-Aznar A, Alvarez-Sabin J, Fernandez-Cadenas I, Ribo M, Molina CA, Lo EH, Montaner J (2006) Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke J Cereb Circ 37:1399–1406

    Article  CAS  Google Scholar 

  30. Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke J Cereb Circ 29:1020–1030

    Article  CAS  Google Scholar 

  31. Gurney KJ, Estrada EY, Rosenberg GA (2006) Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol Dis 23:87–96

    Article  PubMed  CAS  Google Scholar 

  32. Suzuki Y, Nagai N, Yamakawa K, Kawakami J, Lijnen HR, Umemura K (2009) Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. Blood 114:3352–3358

    Article  PubMed  CAS  Google Scholar 

  33. Liu H, Kitazato KT, Uno M, Yagi K, Kanematsu Y, Tamura T, Tada Y, Kinouchi T, Nagahiro S (2008) Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in vivo and in vitro studies. J Hypertens 26:1435–1445

    Article  PubMed  CAS  Google Scholar 

  34. Engelhorn T, Doerfler A, Heusch G, Schulz R (2006) Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats. Neurosci Lett 406:92–96

    Article  PubMed  CAS  Google Scholar 

  35. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab Off J Int Soc Cerebral Blood Flow Metab 20:1681–1689

    Article  CAS  Google Scholar 

  36. Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295:2387–2392

    Article  PubMed  CAS  Google Scholar 

  37. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494

    Article  PubMed  CAS  Google Scholar 

  38. Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M, Razhagi A, Miller K, Gearing A (2001) Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 893:104–112

    Article  PubMed  CAS  Google Scholar 

  39. Kelly-Cobbs AI, Prakash R, Li W, Pillai B, Hafez S, Coucha M, Johnson MH, Ogbi SN, Fagan SC, Ergul A (2013) Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes. Am J Physiol Heart Circ Physiol 304:H806–H815

    Article  PubMed  CAS  Google Scholar 

  40. Jian Liu K, Rosenberg GA (2005) Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med 39:71–80

    Article  PubMed  CAS  Google Scholar 

  41. Engelhorn T, Goerike S, Doerfler A, Okorn C, Forsting M, Heusch G, Schulz R (2004) The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats. J Cereb Blood Flow Metab Off J Int Soc Cerebral Blood Flow Metab 24:467–474

    Article  Google Scholar 

  42. Sutherland BA, Papadakis M, Chen RL, Buchan AM (2011) Cerebral blood flow alteration in neuroprotection following cerebral ischaemia. J Physiol 589:4105–4114

    Article  PubMed  CAS  Google Scholar 

  43. Suzuki Y (2010) Role of tissue-type plasminogen activator in ischemic stroke. J Pharmacol Sci 113:203–207

    Article  PubMed  CAS  Google Scholar 

  44. Hallenbeck JM (2002) The many faces of tumor necrosis factor in stroke. Nat Med 8:1363–1368

    Article  PubMed  CAS  Google Scholar 

  45. Shohami E, Ginis I, Hallenbeck JM (1999) Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev 10:119–130

    Article  PubMed  CAS  Google Scholar 

  46. Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, Moskowitz MA (1996) Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 16:981–987

    Article  CAS  Google Scholar 

  47. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101:731–736

    Article  PubMed  CAS  Google Scholar 

  48. Yamakawa H, Jezova M, Ando H, Saavedra JM (2003) Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 23:371–380

    Article  CAS  Google Scholar 

  49. Sanz-Rosa D, Oubina MP, Cediel E, de Las Heras N, Vegazo O, Jimenez J, Lahera V, Cachofeiro V (2005) Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system. Am J Physiol Heart Circ Physiol 288:H111–H115

    Article  PubMed  CAS  Google Scholar 

  50. Sandset EC, Bath PM, Boysen G, Jatuzis D, Korv J, Luders S, Murray GD, Richter PS, Roine RO, Terent A, Thijs V, Berge E (2011) The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet 377:741–750

    Article  PubMed  CAS  Google Scholar 

  51. Alhusban A, Kozak A, Ergul A, Fagan SC (2013) AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediator. J Pharmacol Exp Ther 344:348–359

    Article  PubMed  CAS  Google Scholar 

  52. Zhou J, Pavel J, Macova M, Yu ZX, Imboden H, Ge L, Nishioku T, Dou J, Delgiacco E, Saavedra JM (2006) AT1 receptor blockade regulates the local angiotensin II system in cerebral microvessels from spontaneously hypertensive rats. Stroke J Cereb Circ 37:1271–1276

    Article  CAS  Google Scholar 

  53. Steckelings UM, Paulis L, Namsolleck P, Unger T (2012) AT2 receptor agonists: hypertension and beyond. Curr Opin Nephrol Hypertens 21:142–146

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by the Veterans Affairs Merit Review (SCF, BX000891 and AE, BX000347) and NIH—NINDS (SCF, NS063965 and AE, NS054688). Adviye Ergul is a research pharmacologist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia.

Conflict of interest

SCF is a consultant for and has received funding from Pfizer. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Author information

Authors and Affiliations

  1. Charlie Norwood VA Medical Center, Augusta, GA, USA

    Tauheed Ishrat, Bindu Pillai, Adviye Ergul, Sherif Hafez & Susan C. Fagan

  2. Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, HM 1212, 1120 15th St., Augusta, GA, 30912, USA

    Tauheed Ishrat, Bindu Pillai, Adviye Ergul, Sherif Hafez & Susan C. Fagan

  3. Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

    Adviye Ergul

  4. Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

    Susan C. Fagan

Authors
  1. Tauheed Ishrat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bindu Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adviye Ergul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sherif Hafez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan C. Fagan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan C. Fagan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishrat, T., Pillai, B., Ergul, A. et al. Candesartan Reduces the Hemorrhage Associated with Delayed Tissue Plasminogen Activator Treatment in Rat Embolic Stroke. Neurochem Res 38, 2668–2677 (2013). https://doi.org/10.1007/s11064-013-1185-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1185-y

Keywords

Search

Navigation