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Pressure under control

Researchers from USP remove from the brains of rats a molecule that is more effective than bradykinin in fighting hypertension

Almost half a century after a group of Brazilian researchers discovered bradykinin, a molecule that has become essential in the manufacturing of the presently most used medicines for controlling high blood pressure, another team has arrived at results that, in principle, mean an advance in the fight against hypertension. A peptide (a fragment of a protein) that was given the name of hemopressine may be up to a hundred times more powerful than bradykinin in bringing down blood pressure and may inspire a generation of medicines that are more effective and have fewer side effects. The drugs employed today in the treatment hypertension offer risks of causing sexual impotence, myocardial infarct, mood alterations and concentration difficulties.

“Hemopressine is bradykinin’s granddaughter,” says the study’s coordinator, pharmacist Emer Suavinho Ferro, from the Biomedical Sciences Institute (ICB) of the University of São Paulo (USP), the results of which will be published in the Journal of Biological Chemistry. In creating this kinship between the molecules, Ferro is referring to the generations of researchers who have worked on this theme, starting with Maurício Oscar da Rocha e Silva (1910-1983), who in 1948 identified and purified bradykinin in the venom of the jararaca (Bothrops jararaca) with another researcher from the São Paulo Biological Institute, Wilson Teixeira Beraldo (1917-1998). Rocha e Silva supervised the doctorate of Antonio Martins de Camargo, who is nowadays at the Butantan Institute. The discoverer of a molecule with antihypertensive effects, it was Camargo who supervised Ferro.

In the 60’s, Rocha e Silva’s work won reinforcement from another disciple, Sérgio Henrique Ferreira, who is today at USP’s School of Medicine in Ribeirão Preto. He isolated an active principle capable of intensifying the response to bradykinin, known as the Bradykinin Potentiating Factor (BPF). It was not easy to convince other scientists that bradykinin had a future. Quite a future, in fact: it is estimated that captopril, the anti-hypertensive made using the potentiating bradykinin, generates world-wide sales of US$ 5 billion a year for the American laboratory Bristol-Myers Squibb, which has held the patent since it produced a synthetic version in 1977.

Kinds of action
The tests on animals carried out at the ICB proved the effectiveness of hemopressine in lowering blood pressure, but there is still much research to be done, until new medicines using this peptide are created; its name is a mixture of hemo (in a reference to its predecessor protein, hemoglobin) and pressine (by virtue of its effect on blood pressure). For the time being, there are only a few hypotheses on the mechanism for the action of this molecule, studied thoroughly by biologist Vanessa Rioli, from the Federal University of São Paulo (Unifesp), who is studying for a doctorate under Ferro.

In general terms, the control of blood pressures is centered on angiotensin I, a hormone produced in the bloodstream. When the blood passes through the lungs, the angiotensin converting enzyme (ECA) transforms angiotensin I into angiotensin II, an enzyme pointed out as the main culprit for making the arteries become narrower and for stimulating the release of hormones that raise the blood pressure. The medicines against high blood pressure prevent the ACE from breaking up the angiotensin I. Accordingly, they postpone the production of angiotensin II and conserve the bradykinin, which is a powerful vasodilator, which increases the diameter of the arteries and so expands the space for the blood to circulate, lowering the pressure.

With hemopressine, the reactions become more complex. It is believed that the peptide may act directly as a protagonist of the mechanisms for the control of blood pressure, perhaps by spurring the relaxation of the arteries, or indirectly, by diverting attention towards itself, like a sort of scapegoat, interacting with the ACE and being itself (the hemopressine) broken up. The ACE would thus stop acting on the bradykinin and angiotensin I, which would be free to keep the pressure steady.

The team from the ICB hit the road that was to lead to these results three years ago, when they started to study the way that two enzymes, thimet-oligopeptidase and neurolysin, degrade peptides. Made inactive, the two enzymes were used as bait for other peptides from rats’ brains – the brain is where there is a greater diversity of peptides. Afterwards, the researchers filtered the connected molecules – complexes of enzyme and peptide -, leaving aside those that remained isolated. In the following stage, the Mass Spectroscopy Laboratory of the Chemistry Institute of the Campinas State University (Unicamp) sequenced 16 peptides that seemed to be connected to the enzymes. Of the three now synthesized (the other 13 are waiting for more in-depth studies), two showed no novelty and have been discarded.

The hypotensive potential of the peptide that was left over from this selection only became clear when it was put into contact with the angiotensin converting enzyme, ACE, which also manages to break up bradykinin. The ACE broke up the hitherto anonymous peptide 11 times more quickly than bradykinin, and 6.7 times more quickly than angiotensin I – a sign that hemopressine may really act in an indirect way, by diverting attention to itself.

The peptide worked better than had been imagined in the two tests that it was put to, with anesthetized and non-anesthetized rats. In work done with Unicamp and the Heart Institute (Incor) of USP’s School of Medicine, a dose of hemopressine a hundred times smaller than one of bradykinin, applied in the left femoral vein of the anesthetized rats, brought about the same fall in blood pressure.

With non-anesthetized rats, the potency of hemopressine is ten times smaller than bradykinin – an indication that the central nervous system regulates the action of hemopressine differently from the way it does with other molecules. “We confirmed the control of the central nervous system by means of leaving the vagus nerve of the non-anesthetized animals out of action, which made the hemopressine just as potent as bradykinin in the reduction of blood pressure,” the researcher notes.

The team from USP went in with a patent request for hemopressine, so as to prevent a foreign company from keeping the dividends of the discovery, such as happened with bradykinin. “We hope that, this time, the story will be different,” says Ferro.

The project
Molecular and Cellular Bases of Peptidase Biology (nº 99/01983-9); Modality Regular research benefit line; Coordinator Emer Suavinho Ferro – ICB/USP; Investment R$ 509,849.14