A promising strategy to treat hypertension is beginning to be defined by a team led by Dr. Robson dos Santos of the Federal University of Minas Gerais (UFMG), Institute of Biological Sciences. In an article published in the April issue of the journal Circulation Research, one of the most highly respected publications in the area of cardiovascular research, the team described a small molecule that is produced naturally by the body and causes blood vessels to relax and blood pressure to decrease. This molecule, which is a peptide (protein fragment) called alamandine, adds to the already complex biochemical mechanism that regulates blood pressure. Its discovery opens up the possibility of exploring a new form of control different from those of medications currently available.
Most anti-hypertensive drugs in use today act to reduce the blood pressure on the inner walls of blood vessels in two ways: (1) by blocking the action of compounds that make the vessels contract and raise blood pressure; or (2) by stimulating a reduction in blood volume through elimination of its water content in urine. Some 20% of the adult population of Brazil and half of those over age 60 have high blood pressure, and Dr. Santos and his group think it may be possible to control it by using a different strategy. Instead of stopping the action of compounds that raise blood pressure, they are attempting to increase the blood concentration of molecules such as alamandine, which decrease pressure.
The researchers believe that alamandine can act in conjunction with another peptide that lowers blood pressure: angiotensin 1-7, which Dr. Santos helped to identify in the late 1980s. It has been known since the mid-20th century that, in general, blood pressure is controlled by the action of the so-called angiotensin peptides, which function as hormones, and act on the cells of the blood vessel wall. Under situations of psychological stress or conditions that alter the concentration of salts or the volume of fluid in the blood (diarrhea and bleeding), the kidneys begin to produce an enzyme called renin, which activates a cascading production of some forms of angiotensin that are able to raise the pressure. When activated occasionally, this mechanism is essential to maintaining the health of the organism. But it becomes harmful if activation is continuous.
Until the 1980s, it was believed that the biochemical mechanism, known as the renin-angiotensin system, acted exclusively as a vasoconstrictor and that its only function was to increase blood pressure. This began to change when Dr. Santos did his post-doctoral training at the Cleveland Clinic Foundation in the United States. He and other researchers there identified a form of blood angiotensin — angiotensin 1-7, part of the renin-angiotensin system — which made the vessel muscles relax and the pressure decrease. “Since then we have become attentive to the presence of other peptides that produce vasodilation,” says Dr. Santos.
He began to suspect the existence of alamandine in 2008, when one of his colleagues, the German researcher Joachim Jankowski, discovered another component of this complicated system, angiotensin A, from which alamandine is produced. But he preferred to wait five years before publishing the discovery, until he could identify the specific receptor to which it is connected and better understand its operation. Today we know that both alamandine and angiotensin 1-7 stimulate the cells lining the inside of blood vessels to produce nitric oxide, a gas that relaxes the muscle wall of the arteries. For this reason, Dr. Santos is working to develop compounds that increase the concentration of both in the blood and improve blood pressure control. “We believe that angiotensin 1-7 and alamandine can act together and, better yet, we hope that one can increase the effect of the other,” says Dr. Santos. He thinks it may be possible to develop compounds with applications that go beyond hypertension, since angiotensin 1-7 also helps reduce the level of certain forms of cholesterol and increase the cell’s use of glucose, which is deficient in most hypertensives.
“The discovery of this molecule may lead to a new class of drugs indicated for cases where traditional remedies do not work as well,” says Dr. Maria Claudia Irigoyen, Chief of the University of São Paulo (USP) Heart Institute’s Experimental Hypertension Laboratory. To her, the fact that alamandine binds itself to different receptors in the cells of the blood vessels increases its range of therapeutic action.
The work of the Minas Gerais team is now focused on two fronts. One is basic, aimed at identifying the alamandine signal pathway within cells, and the other is clinical, aimed at testing the action of this molecule in people with hypertension. Currently a compound based on angiotensin 1-7, developed by Dr. Santos’s group, has advanced to human testing — it has already been given to pregnant women with pre-eclampsia to regulate the peptide’s level in the blood and control blood pressure (see Pesquisa FAPESP issue No. 203), and tests with alamandine will begin later this year. “Because this peptide is produced by the body itself, we believe that there will be no toxic effects. Therefore, we can skip the toxicology tests usually performed on animals and go straight to clinical trials,” says Dr. Santos, who coordinates the National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar).
A former student of Dr. Eduardo Moacyr Krieger, a leading Brazilian expert on hypertension, Dr. Santos heads a select group of researchers who are dedicated to taking discoveries from the experimental phase to patients. He is concerned about the pace of research in this area in Brazil. “I fear that what will happen to us is what happened with captopril, even though our compound is already protected by patents,” says Dr. Santos, who is uneasy about delays resulting from insufficient financial support and bureaucratic obstacles to innovation in academia and business.
In the 1960s, Sérgio Ferreira, a pharmacologist at USP Ribeirão Preto, identified a molecule (the bradykinin-potentiating factor) in the venom of the Brazilian pit viper (Bothrops jararaca) that blocks the formation of angiotensin II and led to the development of the captopril antihypertensive. At the time he was not concerned about seeking a patent, and the profit from producing the drug went to a foreign laboratory. “If we do not move quickly,” says Dr. Santos, “we will lose the lead again.”
LAUTNER, R. et al. Discovery and characterization of alamandine, a novel component of the renin-angiotensin system. Circulation Research, v. 112, p. 1104-11. 2013.