Concluding Remarks

  • Robson Augusto Souza SantosEmail author


As illustrated in many chapters of this book, angiotensin-(1-7) is now well established and considered an important player of the renin–angiotensin system (RAS). Due to its pleiotropic aspect and consequent beneficial effects in the body, this peptide is a target for developing new medications aimed to treat cardiovascular, renal, and metabolic diseases. The use of Ang-(1-7) by itself as a drug has been hampered by the naive concept that since it has a short half-life in plasma, it cannot be used as a drug. However, the action of a peptide in the body is not proportional to its half-life in the blood as the traditional allopathic drugs. For example, the signaling cascade activated by a peptide acting on its receptor may have a kinetics completely different from the half-life of the free peptide in the blood. Likewise, the receptor-bound peptide does not follow the classical linear relationship expected from evaluations using conventional pharmacokinetics models. Actually, as illustrated in different chapters, there are many publications showing that a single daily oral administration of the inclusion compound Ang-(1-7)/HPB-cyclodextrin is capable of producing beneficial effects in rodents, including improved heart function after myocardial infarction and reduction in blood pressure in SHR) More recently the same formulation was tested in humans and a significant improvement of recovery from a supramaximal physical exercise was observed. These data did not fit with a half-life of seconds for the peptide. The potential role of clinical use of the stimulation of the Ang-(1-7) receptor Mas was recently emphasized by an outstanding publication of a Mayo Clinics’ group. In their manuscript, a single polypeptide comprising a fragment of BNP associated with the angiotensin-(1-7) sequence was demonstrated to behave as a Mas agonist and more important, to have a dramatic gain in the efficacy on the blood pressure and other parameters. The effect of the polypeptide was blocked by the Mas antagonist A-779. This manuscript opens new venues to explore the potential of Mas agonists as beneficial drugs in the cardiovascular field. In addition to these exciting new findings, the rather recent discovery of the angiotensin derivative alamandine by our research group adds new possibilities to explore the physiology and pharmacological potential of the protecting arm of the RAS.


  1. 1.
    Acuña M, Pessina P, Olguin H, Cabrera D, Vio CP, Bader M, Muñoz-Canoves P, Santos RA, Cabello-Verrugio C, Brandan E. Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. Hum Mol Genet. 2014;23:1237–49. Scholar
  2. 2.
    Andrade J, de Lemos F, da Pires S, Millán R, de Sousa F, Guimarães A, Qureshi M, Feltenberger J, de Paula A, Neto J, Lopes M, de Andrade H, Santos R, Santos S. Proteomic white adipose tissue analysis of obese mice fed with a high-fat diet and treated with oral angiotensin-(1-7). Peptides. 2014;60:56–62. Scholar
  3. 3.
    Andrade J, Paraíso A, Garcia Z, Ferreira A, Sinisterra R, Sousa FB, Guimarães A, de Paula A, Campagnole-Santos M, dos Santos R, Santos S. Cross talk between angiotensin-(1-7)/Mas axis and sirtuins in adipose tissue and metabolism of high-fat feed mice. Peptides. 2014;55:158–65. Scholar
  4. 4.
    Becker L, Totou N, Moura S, Kangussu L, Millán R, Campagnole-Santos M, Coelho D, Motta-Santos D, Santos R. Eccentric overload muscle damage is attenuated by a Novel Angiotensin- (1-7) Treatment. Int J Sports Med. 2018;39:743–8. Scholar
  5. 5.
    Bennion DM, Jones CH, Donnangelo LL, Graham JT, Isenberg JD, Dang AN, Rodriguez V, Sinisterra RD, Sousa FB, Santos RA, Sumners C. Neuroprotection by post-stroke administration of an oral formulation of angiotensin-(1-7) in ischaemic stroke. Exp Physiol. 2018;103:916–23. Scholar
  6. 6.
    Bertagnolli M, Casali KR, Sousa FB, Rigatto K, Becker L, Santos S, Dias LD, Pinto G, Dartora DR, Schaan BD, Milan R, Irigoyen M, Santos R. An orally active angiotensin-(1-7) inclusion compound and exercise training produce similar cardiovascular effects in spontaneously hypertensive rats. Peptides. 2014;51:65–73. Scholar
  7. 7.
    Feltenberger J, Andrade J, Paraíso A, Barros L, Filho A, Sinisterra R, Sousa FB, Guimarães A, de Paula A, Campagnole-Santos M, Qureshi M, dos Santos R, Santos S. Oral formulation of angiotensin-(1-7) improves lipid metabolism and prevents high-fat diet–induced hepatic steatosis and inflammation in Mice. Hypertension. 2013;62:324–30. Scholar
  8. 8.
    Fraga-Silva R, Costa-Fraga FP, Sousa FB, Alenina N, Bader M, Sinisterra RD, Santos RA. An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect. Clinics. 2011;66:837–41. Scholar
  9. 9.
    Fraga-Silva R, Savergnini S, Montecucco F, Nencioni A, Caffa I, Soncini D, Costa-Fraga F, Sousa F, Sinisterra R, Capettini L, Lenglet S, Galan K, Pelli G, Bertolotto M, Pende A, Spinella G, Pane B, Dallegri F, Palombo D, Mach F, Stergiopulos N, Santos R, da Silva R. Treatment with Angiotensin-(1-7) reduces inflammation in carotid atherosclerotic plaques. Thromb Haemost. 2014;111:736–47. Scholar
  10. 10.
    Fraga-Silva RA, Costa-Fraga FP, Savergnini SQ, Sousa FB, Montecucco F, Silva D, Sinisterra RD, Mach F, Stergiopulos N, Silva RF, Santos R. An oral formulation of angiotensin-(1-7) reverses Corpus Cavernosum damages induced by hypercholesterolemia. J Sex Med. 2013;10:2430–42. Scholar
  11. 11.
    Lautner R, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, Jankowski J, Jankowski V, Sousa F, Alzamora A, Soares E, Barbosa C, Kjeldsen F, Oliveira A, Braga J, Savergnini S, Maia G, Peluso A, Passos-Silva D, Ferreira A, Alves F, Martins A, Raizada M, Paula R, Motta-Santos D, Klempin F, Kemplin F, Pimenta A, Alenina N, Sinisterra R, Bader M, Campagnole-Santos M, Santos RA. Discovery and characterization of Alamandine. Circ Res. 2013;112:1104–11. Scholar
  12. 12.
    Marques FD, Ferreira AJ, Sinisterra R, Jacoby BA, Sousa FB, Caliari MV, Silva G, Melo MB, Nadu AP, Souza LE, Irigoyen M, Almeida AP, Santos R. An oral formulation of angiotensin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. Hypertension. 2011;57:477–83. Scholar
  13. 13.
    Marques FD, Melo MB, Souza LE, Irigoyen MC, Sinisterra RD, de Sousa FB, Savergnini SQ, Braga VB, Ferreira AJ, Santos RA. Beneficial effects of long-term administration of an oral formulation of angiotensin-(1-7) in infarcted rats. Int J Hypertens. 2012;2012:795452. Scholar
  14. 14.
    Meems LM, Andersen IA, Pan S, Harty G, Chen Y, Zheng Y, Harders GE, Ichiki T, Heublein DM, Iyer SR, Sangaralingham JS, McCormick DJ, Burnett JC. Design, synthesis, and actions of an innovative bispecific designer peptide. Hypertension. 2019;73(4):900–9. Scholar
  15. 15.
    Sabharwal R, Cicha MZ, nisterra RD, Sousa FB, Santos RA, Chapleau MW. Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy. Clin Sci. 2014;127:101–9. Scholar
  16. 16.
    Santos C, Santos S, Ferreira A, Botion LM, Santos R, Campagnole-Santos M. Association of an oral formulation of angiotensin-(1-7) with atenolol improves lipid metabolism in hypertensive rats. Peptides. 2013;43:155–9. Scholar
  17. 17.
    Santos S, Andrade J, Fernandes L, Sinisterra R, Sousa FB, Feltenberger J, Alvarez-Leite J, Santos R. Oral angiotensin-(1-7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet. Peptides. 2013;46:47–52. Scholar
  18. 18.
    Santos SH, Giani JF, Burghi V, Miquet JG, Qadri F, Braga JF, Todiras M, Kotnik K, Alenina N, Dominici FP, Santos RA, Bader M. Oral administration of angiotensin-(1-7) ameliorates type 2 diabetes in rats. J Mol Med. 2014;92:255–65. Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.National Institute of Science and Technology in Nano Biopharmaceutics – Department of Physiology and BiophysicsBiological Sciences Institute, Federal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Department of Physiology and PharmacologyBiological Sciences Institute, Federal University of Minas GeraisBelo HorizonteBrazil

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