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2000
Volume 32, Issue 4
  • ISSN: 0929-8665
  • E-ISSN: 1875-5305

Abstract

Introduction

Diminazene aceturate (DIZE) was described as an angiotensin-converting enzyme 2 (ACE2) activator. ACE2/Angiotensin-(1-7)/Mas receptor axis presents protective actions on cardiovascular diseases and plays an important modulatory role in the neurobiology of mood and anxiety disorders.

Objectives

To evaluate the effects of chronic intracerebroventricular (ICV) treatment with DIZE on blood pressure, anxiety- and depression-like behaviors in hypertensive transgenic (mRen2)27 rats (TGR).

Methods

Male TGR and Sprague-Dawley rats (10-12 weeks old) were subjected to chronic ICV infusion of DIZE (1.0 µg/h for 7 days). Blood pressure and heart rate were measured by tail plethysmography and anxiety- and depression-like behaviors were evaluated through elevated plus maze, marble burying and forced swim tests, respectively.

Results

Treatment with DIZE induced a significant reduction in mean arterial pressure in both TGR and SD rats. A decrease in heart rate was only observed in the hypertensive animals. Additionally, treatment with DIZE attenuated the anxiety- and depression-like behaviors that were observed in TGR.

Conclusion

DIZE has central anti-hypertensive, anxiolytic, and anti-depressive effects.

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2025-02-24
2025-12-17
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References

  1. DonoghueM. HsiehF. BaronasE. GodboutK. GosselinM. StaglianoN. DonovanM. WoolfB. RobisonK. JeyaseelanR. BreitbartR.E. ActonS. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ. Res.2000875E1E910.1161/01.RES.87.5.e110969042
    [Google Scholar]
  2. TipnisS.R. HooperN.M. HydeR. KarranE. ChristieG. TurnerA.J. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase.J. Biol. Chem.200027543332383324310.1074/jbc.M00261520010924499
    [Google Scholar]
  3. PatelV.B. ZhongJ.C. GrantM.B. OuditG.Y. Role of the ACE2/Angiotensin 1–7 axis of the renin–angiotensin system in heart failure.Circ. Res.201611881313132610.1161/CIRCRESAHA.116.30770827081112
    [Google Scholar]
  4. SantosR.A.S. SampaioW.O. AlzamoraA.C. Motta-SantosD. AleninaN. BaderM. Campagnole-SantosM.J. The ACE2/Angiotensin-(1–7)/MAS axis of the renin-angiotensin system: Focus on angiotensin-(1–7).Physiol. Rev.201898150555310.1152/physrev.00023.201629351514
    [Google Scholar]
  5. Verano-BragaT. MartinsA.L.V. Motta-SantosD. Campagnole-SantosM.J. SantosR.A.S. ACE2 in the renin–angiotensin system.Clin. Sci.2020134233063307810.1042/CS2020047833264412
    [Google Scholar]
  6. MullinsJ.J. PetersJ. GantenD. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene.Nature1990344626654154410.1038/344541a02181319
    [Google Scholar]
  7. LangheinrichM. LeeM.A. BöhmM. PintoY.M. GantenD. PaulM. The hypertensive Ren-2 transgenic rat TGR (mREN2) 27 in hypertension research characteristics and functional aspects.Am. J. Hypertens.19969550651210.1016/0895‑7061(95)00400‑98735183
    [Google Scholar]
  8. LeeM.A. BöhmM. PaulM. BaderM. GantenU. GantenD. Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27.Am. J. Physiol. Endocrinol. Metab.19962706E919E92910.1152/ajpendo.1996.270.6.E9198764174
    [Google Scholar]
  9. BishopJ. KiernanL.A. MontgomeryH.E. GohlkeP. McEwanJ.R. Raised blood pressure, not renin–angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats.Cardiovasc. Res.2000471576710.1016/S0008‑6363(00)00063‑810869530
    [Google Scholar]
  10. DeMarcoV.G. JohnsonM.S. HabibiJ. PulakatL. GulR. HaydenM.R. TilmonR.D. DellspergerK.C. WinerN. Whaley-ConnellA.T. SowersJ.R. Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat.Am. J. Physiol. Heart Circ. Physiol.20113001H181H19010.1152/ajpheart.00883.201021057043
    [Google Scholar]
  11. Almeida-SantosA.F. KangussuL.M. MoreiraF.A. SantosR.A.S. AguiarD.C. Campagnole-SantosM.J. Anxiolytic- and antidepressant-like effects of angiotensin-(1–7) in hypertensive transgenic (mRen2)27 rats.Clin. Sci. 2016130141247125510.1042/CS2016011627129185
    [Google Scholar]
  12. KuriakoseS. MulemeH.M. OnyilaghaC. SinghR. JiaP. UzonnaJ.E. Diminazene aceturate (Berenil) modulates the host cellular and inflammatory responses to Trypanosoma congolense infection.PLoS One2012711e4869610.1371/journal.pone.004869623144931
    [Google Scholar]
  13. GjymishkaA KuleminaLV ShenoyV KatovichMJ OstrovDA RaizadaMK Diminazene aceturate is an ACE2 activator and a novel antihypertensive drug.FASEB J2010241032.31032.310.1096/fasebj.24.1_supplement.1032.3
    [Google Scholar]
  14. QaradakhiT. GadanecL.K. McSweeneyK.R. TaceyA. ApostolopoulosV. LevingerI. RimarovaK. EgomE.E. RodrigoL. KruzliakP. KubatkaP. ZulliA. The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases.Clin. Exp. Pharmacol. Physiol.202047575175810.1111/1440‑1681.1325131901211
    [Google Scholar]
  15. De MariaM.L. AraújoL.D. Fraga-SilvaR.A. PereiraL.A. RibeiroH.J. MenezesG.B. ShenoyV. RaizadaM.K. FerreiraA.J. Anti-hypertensive effects of diminazene aceturate: An Angiotensin- Converting enzyme 2 activator in rats.Protein Pept. Lett.201623191610.2174/092986652266615101313055026458404
    [Google Scholar]
  16. ShenoyV. GjymishkaA. JarajapuY.P. QiY. AfzalA. RigattoK. FerreiraA.J. Fraga-SilvaR.A. KearnsP. DouglasJ.Y. AgarwalD. MubarakK.K. BradfordC. KennedyW.R. JunJ.Y. RathinasabapathyA. BruceE. GuptaD. CardounelA.J. MoccoJ. PatelJ.M. FrancisJ. GrantM.B. KatovichM.J. RaizadaM.K. Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models.Am. J. Respir. Crit. Care Med.2013187664865710.1164/rccm.201205‑0880OC23370913
    [Google Scholar]
  17. RigattoK. CasaliK.R. ShenoyV. KatovichM.J. RaizadaM.K. Diminazene aceturate improves autonomic modulation in pulmonary hypertension.Eur. J. Pharmacol.20137131-3899310.1016/j.ejphar.2013.04.01723665493
    [Google Scholar]
  18. QiY. ZhangJ. Cole-JeffreyC.T. ShenoyV. EspejoA. HannaM. SongC. PepineC.J. KatovichM.J. RaizadaM.K. Diminazene aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology.Hypertension201362474675210.1161/HYPERTENSIONAHA.113.0133723959549
    [Google Scholar]
  19. CastardeliC. SartórioC.L. PimentelE.B. ForechiL. MillJ.G. The ACE2 activator diminazene aceturate (DIZE) improves left ventricular diastolic dysfunction following myocardial infarction in rats.Biomed. Pharmacother.201810721221810.1016/j.biopha.2018.07.17030092400
    [Google Scholar]
  20. BadaeN.M. El NaggarA.S. El SayedS.M. Is the cardioprotective effect of the ACE2 activator diminazene aceturate more potent than the ACE inhibitor enalapril on acute myocardial infarction in rats?Can. J. Physiol. Pharmacol.201997763864610.1139/cjpp‑2019‑007830840489
    [Google Scholar]
  21. Fraga-SilvaR.A. Costa-FragaF.P. MontecuccoF. SturnyM. FayeY. MachF. PelliG. ShenoyV. da SilvaR.F. RaizadaM.K. SantosR.A.S. StergiopulosN. Diminazene protects corpus cavernosum against hypercholesterolemia-induced injury.J. Sex. Med.201512228930210.1111/jsm.1275725411084
    [Google Scholar]
  22. Fraga-SilvaR.A. MontecuccoF. Costa-FragaF.P. NencioniA. CaffaI. BraginaM.E. MachF. RaizadaM.K. SantosR.A.S. da SilvaR.F. StergiopulosN. Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice.Vascul. Pharmacol.20157410311310.1016/j.vph.2015.08.01426304699
    [Google Scholar]
  23. StachowiczA. WiśniewskaA. KuśK. BiałasM. ŁomnickaM. Totoń-ŻurańskaJ. KiepuraA. StachyraK. SuskiM. Bujak-GiżyckaB. JawieńJ. OlszaneckiR. Diminazene aceturate stabilizes atherosclerotic plaque and attenuates hepatic steatosis in apoE-knockout mice by influencing macrophages polarization and taurine biosynthesis.Int. J. Mol. Sci.20212211586110.3390/ijms2211586134070749
    [Google Scholar]
  24. CoutinhoD.C.O. Monnerat-CahliG. FerreiraA.J. MedeiE. Activation of angiotensin-converting enzyme 2 improves cardiac electrical changes in ventricular repolarization in streptozotocin-induced hyperglycaemic rats.Europace201416111689169610.1093/europace/euu07024741027
    [Google Scholar]
  25. ZhangY. LiuJ. LuoJ.Y. TianX.Y. CheangW.S. XuJ. LauC.W. WangL. WongW.T. WongC.M. LanH.Y. YaoX. RaizadaM.K. HuangY. Upregulation of angiotensin (1-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes.Antioxid. Redox Signal.2015231188089210.1089/ars.2014.607025867182
    [Google Scholar]
  26. GoruS.K. KadakolA. MalekV. PandeyA. SharmaN. GaikwadA.B. Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes.Br. J. Pharmacol.2017174183118313010.1111/bph.1394628688122
    [Google Scholar]
  27. MalekM. NematbakhshM. The preventive effects of diminazene aceturate in renal ischemia/reperfusion injury in male and female rats.Adv. Prev. Med.201420141910.1155/2014/74064725478235
    [Google Scholar]
  28. Silva de AlmeidaT.C. LanzaK. da Silva FilhaR. C CamposL.M.C. FonsecaE.G. ChagasM.W. RochaN.P. de SáM.A. VieiraM.A.R. CaliariM.V. KangussuL.M. FerreiraA.J. Simões E SilvaA.C. ACE2 activator diminazene aceturate exerts renoprotective effects in gentamicin-induced acute renal injury in rats.Clin. Sci. 2020134233093310610.1042/CS2020102233206153
    [Google Scholar]
  29. MeccaA.P. RegenhardtR.W. O’ConnorT.E. JosephJ.P. RaizadaM.K. KatovichM.J. SumnersC. Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke.Exp. Physiol.201196101084109610.1113/expphysiol.2011.05857821685445
    [Google Scholar]
  30. BennionD.M. HaltiganE.A. IrwinA.J. DonnangeloL.L. RegenhardtR.W. PioquintoD.J. PurichD.L. SumnersC. Activation of the neuroprotective angiotensin-converting enzyme 2 in rat ischemic stroke.Hypertension201566114114810.1161/HYPERTENSIONAHA.115.0518525941346
    [Google Scholar]
  31. KamelA.S. AbdelkaderN.F. Abd El-RahmanS.S. EmaraM. ZakiH.F. KhattabM.M. Stimulation of ACE2/ANG(1–7)/Mas axis by diminazene ameliorates Alzheimer’s disease in the D-Galactose-ovariectomized rat model: Role of PI3K/Akt pathway.Mol. Neurobiol.201855108188820210.1007/s12035‑018‑0966‑329516284
    [Google Scholar]
  32. DuanR. XueX. ZhangQ.Q. WangS.Y. GongP.Y. YanE. JiangT. ZhangY.D. ACE2 activator diminazene aceturate ameliorates Alzheimer’s disease-like neuropathology and rescues cognitive impairment in SAMP8 mice.Aging20201214148191482910.18632/aging.10354432701063
    [Google Scholar]
  33. EvansC.E. MinersJ.S. PivaG. WillisC.L. HeardD.M. KiddE.J. GoodM.A. KehoeP.G. ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease.Acta Neuropathol.2020139348550210.1007/s00401‑019‑02098‑631982938
    [Google Scholar]
  34. SunX. DengY. GeP. PengQ. SoufianyI. ZhuL. DuanR. Diminazene ameliorates neuroinflammation by suppression of astrocytic miRNA-224-5p/NLRP3 axis in Alzheimer’s disease model.J. Inflamm. Res.2023161639165210.2147/JIR.S40138537092127
    [Google Scholar]
  35. TiwariV. SinghJ. TiwariP. ChaturvediS. GuptaS. MishraA. SinghS. WahajuddinM. HanifK. ShuklaS. ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer’s disease-like phenotypes.Eur. J. Pharmacol.202394617562310.1016/j.ejphar.2023.17562336871666
    [Google Scholar]
  36. WangL. de KloetA.D. PatiD. HillerH. SmithJ.A. PioquintoD.J. LudinJ.A. OhS.P. KatovichM.J. FrazierC.J. RaizadaM.K. KrauseE.G. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.Neuropharmacology201610511412310.1016/j.neuropharm.2015.12.02626767952
    [Google Scholar]
  37. NakagawasaiO. TakahashiK. KoyamaT. YamagataR. NemotoW. Tan-NoK. Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice.Mol. Brain20231615210.1186/s13041‑023‑01040‑y37312182
    [Google Scholar]
  38. PaxinosG. WatsonC. The Rat Brain in Stereotaxic Coordinates6th Edition, Academic Press, San Diego, 2007.
    [Google Scholar]
  39. KregeJ.H. HodginJ.B. HagamanJ.R. SmithiesO. A noninvasive computerized tail-cuff system for measuring blood pressure in mice.Hypertension19952551111111510.1161/01.HYP.25.5.11117737724
    [Google Scholar]
  40. HandleyS.L. MithaniS. Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of 'fear'-motivated behaviour.Naunyn Schmiedebergs Arch. Pharmacol.198432711510.1007/BF005049836149466
    [Google Scholar]
  41. WalfA.A. FryeC.A. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents.Nat. Protoc.20072232232810.1038/nprot.2007.4417406592
    [Google Scholar]
  42. AmadoC.L. AmaralL.B.O. MourãoF.A.G. BaderM. SantosR.A.S. Campagnole-SantosM.J. KangussuL.M. Anxiolytic effect of alamandine in male transgenic rats with low brain angiotensinogen is dependent on activation of MrgD receptors.Horm. Behav.202416310555110.1016/j.yhbeh.2024.10555138678724
    [Google Scholar]
  43. El MarzoukiH. AboussalehY. NajimiM. ChigrF. AhamiA. Effect of cold stress on neurobehavioral and physiological parameters in rats.Front. Physiol.20211266012410.3389/fphys.2021.66012434603068
    [Google Scholar]
  44. CollaA.R.S. RosaJ.M. CunhaM.P. RodriguesA.L.S. Anxiolytic-like effects of ursolic acid in mice.Eur. J. Pharmacol.201575817117610.1016/j.ejphar.2015.03.07725861934
    [Google Scholar]
  45. SartimA.G. SartimM.A. CummingsR.D. Dias-BaruffiM. JocaS.R. Impaired emotional response to stress in mice lacking galectin-1 or galectin-3.Physiol. Behav.202022011286210.1016/j.physbeh.2020.11286232156558
    [Google Scholar]
  46. PorsoltR.D. Le PichonM. JalfreM. Depression: A new animal model sensitive to antidepressant treatments.Nature1977266560473073210.1038/266730a0559941
    [Google Scholar]
  47. CryanJ.F. ValentinoR.J. LuckiI. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test.Neurosci. Biobehav. Rev.2005294-554756910.1016/j.neubiorev.2005.03.00815893822
    [Google Scholar]
  48. KangussuL.M. Almeida-SantosA.F. BaderM. AleninaN. FontesM.A.P. SantosR.A.S. AguiarD.C. Campagnole-SantosM.J. Angiotensin-(1-7) attenuates the anxiety and depression-like behaviors in transgenic rats with low brain angiotensinogen.Behav. Brain Res.2013257253010.1016/j.bbr.2013.09.00324016839
    [Google Scholar]
  49. Almeida-SantosA.F. de MeloL.A. GonçalvesS.C.A. Oliveira AmaralL.B. SantosR.A.S. Campagnole-SantosM.J. KangussuL.M. Alamandine through MrgD receptor induces antidepressant-like effect in transgenic rats with low brain angiotensinogen.Horm. Behav.202112710488010.1016/j.yhbeh.2020.10488033129833
    [Google Scholar]
  50. AbelE.L. BilitzkeP.J. A possible alarm substance in the forced swimming test.Physiol. Behav.199048223323910.1016/0031‑9384(90)90306‑O2255725
    [Google Scholar]
  51. PorsoltR.D. BertinA. JalfreM. “Behavioural despair” in rats and mice: Strain differences and the effects of imipramine.Eur. J. Pharmacol.197851329129410.1016/0014‑2999(78)90414‑4568552
    [Google Scholar]
  52. SlatteryD.A. CryanJ.F. Using the rat forced swim test to assess antidepressant-like activity in rodents.Nat. Protoc.2012761009101410.1038/nprot.2012.04422555240
    [Google Scholar]
  53. BaderM. ZhaoY. SanderM. LeeM.A. BachmannJ. BöhmM. DjavidaniB. PetersJ. MullinsJ.J. GantenD. Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats.Hypertension1992196_pt_268168610.1161/01.HYP.19.6.6811592468
    [Google Scholar]
  54. KangussuL.M. GuimaraesP.S. NaduA.P. MeloM.B. SantosR.A.S. Campagnole-SantosM.J. Activation of angiotensin-(1–7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats.Neuropharmacology201597586610.1016/j.neuropharm.2015.04.03625983274
    [Google Scholar]
  55. VelkoskaE. PatelS.K. BurrellL.M. Angiotensin converting enzyme 2 and diminazene.Curr. Opin. Nephrol. Hypertens.201625538439510.1097/MNH.000000000000025427367913
    [Google Scholar]
  56. KangussuL.M. de AlmeidaT.C.S. PrestesT.R.R. de Andrade De MariaM.L. da Silva FilhaR. VieiraM.A.R. SilvaA.C.S. FerreiraA.J. Beneficial effects of the angiotensin-converting enzyme 2 activator dize in renovascular hypertension.Protein Pept. Lett.201926752353110.2174/092986652666619040512342230950337
    [Google Scholar]
  57. ZhangC. CaoX. WangH. LiZ. ZhangY. The ACE2 activator diminazene aceturate ameliorates colitis by repairing the gut-vascular barrier in mice.Microvasc. Res.202314810454410.1016/j.mvr.2023.10454437127063
    [Google Scholar]
  58. PassagliaP. KanashiroA. Batista SilvaH. NavegantesL.C.C. LacchiniR. CárnioC.E. BrancoL.G.S. Diminazene aceturate attenuates systemic inflammation via microbiota gut-5-HT brain-spleen sympathetic axis in male mice.Brain Behav. Immun.202411910511910.1016/j.bbi.2024.03.03738548186
    [Google Scholar]
  59. SartórioC.L. PimentelE.B. dos SantosR.L. RouverW.N. MillJ.G. Acute hypotensive effect of diminazene aceturate in spontaneously hypertensive rats: Role of NO and Mas receptor.Clin. Exp. Pharmacol. Physiol.202047101723173010.1111/1440‑1681.1336832603499
    [Google Scholar]
  60. BessaA.S.M. JesusÉ.F. NunesA.D.C. PontesC.N.R. LacerdaI.S. CostaJ.M. SouzaE.J. Lino-JúniorR.S. BiancardiM.F. dos SantosF.C.A. PedrinoG.R. ColugnatiD.B. Mazaro-CostaR. MendesE.P. CastroC.H. Stimulation of the ACE2/Ang-(1–7)/Mas axis in hypertensive pregnant rats attenuates cardiovascular dysfunction in adult male offspring.Hypertens. Res.201942121883189310.1038/s41440‑019‑0321‑831506648
    [Google Scholar]
  61. de KloetA.D. CahillK.M. ScottK.A. KrauseE.G. Overexpression of angiotensin converting enzyme 2 reduces anxiety-like behavior in female mice.Physiol. Behav.202022411300210.1016/j.physbeh.2020.11300232525008
    [Google Scholar]
  62. AtsrikuC. WatsonD.G. TetteyJ.N.A. GrantM.H. SkellernG.G. Determination of diminazene aceturate in pharmaceutical formulations by HPLC and identification of related substances by LC/MS.J. Pharm. Biomed. Anal.200230497998610.1016/S0731‑7085(02)00450‑812408888
    [Google Scholar]
  63. DutraJ.B.R. LacerdaI.S. NunesA.D.C. BessaA.S.M. JesusÉ.F. PontesC.N.R. NavesL.M. PedrinoG.R. MendesE.P. Fraga-SilvaR.A. Costa-FragaF.P. StergiopulosN. KangussuL.M. FaracoA.A.G. FerreiraA.J. CastroC.H. p-Aminobenzamidine attenuates cardiovascular dysfunctions in spontaneously hypertensive rats.Life Sci.202230412069310.1016/j.lfs.2022.12069335688180
    [Google Scholar]
  64. HaberP.K. YeM. WysockiJ. MaierC. HaqueS.K. BatlleD. Angiotensin-converting enzyme 2-independent action of presumed angiotensin-converting enzyme 2 activators: Studies in vivo, ex vivo, and in vitro.Hypertension201463477478210.1161/HYPERTENSIONAHA.113.0285624446061
    [Google Scholar]
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  • Article Type:
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Keyword(s): ACE2; anxiety; depression; Diminazene aceturate; hypertension; TGR(mRen2)27
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