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Losing beat

Failure in terminals of neurons keep the heart speeded up

An animal model recently concluded at the University of São Paulo (USP), based on genetically modified mice, indicates one of the causes of severe cardiac insufficiency – a disturbance in which the heart fails to pump blood efficiently. With time, the model may beckon with ways seek alternatives for the treatment and prevention of this problem – one of the forms of heart disease, which kill twice more than all the kinds of cancer together: about 15 million persons a year – and, just in Brazil, 250,000.

Patricia Chakur Brum, the coordinator of the study, which has been accepted for publication in the American Journal of Physiology, disabled in mice two proteins that regulate heartbeats and which are located in the terminals of the neurons that are close to the heart – the alpha-2a and alpha-2c adrenergic receptors, so called for controlling the release of the noradrenaline neurotransmitter, essential for regulating the activity of the cardiac muscle. The approach is innovative, as it interferes only with the activity of the nerve terminals, without altering the proteins produced in the inside of the cardiac muscle.

Last year, during her postgraduate studies at Stanford University-Beckman, in the United States, Patricia suspected that the lack of the two proteins together could cause problems for the heart. “It was already known that the alpha-2a adrenergic receptor would inhibit the release of noradrenaline, but that its lack would not cause cardiac insufficiency”, she says. “Then I tested what would happen if the two receptors didn’t work”. She suppressed – or knocked out, as the geneticists say – from the genome of the mice the genes from which they are made. As a result, the animals show severe cardiac insufficiency, similar to the kind shown in human beings. “The majority of people with chronic cardiac insufficiency also show an excessive increase in the activity of the heart, caused by a larger quantity of noradrenaline is released into the cardiac muscle”, she says.

In the experiment, of the 90 animals studied, all with their receptors knocked out, half died after six months of life. Patricia completed the discovery of the importance of the two alpha receptors by implementing, in the laboratory where she did her postgraduate studies, a model of culture of sympathetic nerve cells and those of the cardiac muscle. “This model is going to make it a lot easier to study the receptors that act outside the heart or even outside it”, comments Brian Kobilka, the head of the laboratory at Stanford University where the Brazilian researcher worked.

Using this technique, Patricia discovered that the alpha-2a and alpha-2c receptors are to be found at different points of the nerve terminals, instead of being concentrated in just one place, as it used to be imagined. This fact suggests distinct mechanisms for regulating the nerve and the cells of the heart.

Avoiding excesses
To understand the advances with this work, one has to look beyond the heart and go into the meanders of the nervous system. This is a system made up of two major branches: the central nervous system (CNS), composed of the nerve structures inside the cranium and the spine, and the peripheral nervous system (PNS), consisting of the nerves spread all over the body. The former controls our vital functions, such as heartbeats and breathing, and the latter takes information for the CNS to carry out the actions necessary for daily life to continue.When we feel fear, faced by a situation of peril, the sympathetic nerve terminals, which are part of the peripheral nervous system, a few millimeters from the heart, release a substance called noradrenaline into the cardiac muscle.

Noradrenaline is produced both in the nerve terminals and in the suprarenal glands – which are located in the kidneys, and also make adrenaline – with similar effects: both prepare the body to flee or to fight, increasing the heartbeats and the rate of breathing, in such a way that the oxygen carried by the blood reaches the muscles quickly. When produced by the nerve terminals, noradrenaline acts as a neurotransmitter, passing on information from one neuron to another, and reaches the cardiac muscle in seconds, accelerating the heartbeats. In the mice with the receptors disabled, the quantity of noradrenaline released in the heart was double that found in normal mice.

The alpha receptors and noradrenaline work in conjunction, as if they were a key and a lock: noradrenaline, when released by the nerve terminals, binds itself to the alpha-2a and alpha-2c receptors, which, in turn, inhibit the release of more noradrenaline, preventing its concentration from going sky high. When the two receptors are missing, there is no way of holding back the exacerbated release of noradrenaline. The consequence: an exacerbated increase takes place in the activity of the cardiac muscle, giving rise to the so-called severe cardiomyopathies, which may lead to cardiac insufficiency. It was precisely this wear in the cardiac muscle that was found in the mice used in the experiment in which the production of the receptors was blocked.

Patricia’s work innovated when she tested the effects of the lack of receptors located outside the heart: previous studies concentrated on the alteration of the expression of receptors located in this organ, like the beta-1 and beta-2 adrenergics. According to the researcher, working with receptors inside the heart suffers from a limitation, as other proteins produced by the organ may react to this shortage and compensate the effect.

Since the beginning of the year, once again installed in USP’s Physical Education and Sports School, Patricia is preparing to study how genetic alterations are related to physical activity, specifically which molecules are activated, disabled or replaced in mice with their receptors disabled – something that it is impossible to do in human beings. “Physical activity regulates the heartbeats, but we still do not know in depth the mechanisms in the molecules and the cells that make this happens”, Patricia comments.

The Project
Role of the Alpha-2 Adrenergic Receptors, a and c subtypes, in Regulating the Release of Neurotransmitters from the Sympathetic Cardiac Nerve Terminals
Grant for postdoctoral studies abroad
Patricia Chakur Brum – Physical Education and Sports School at USP
R$ 108,619.47