Concluding Remarks

Abstract

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.