For decades, we believed that the “steering wheel” of our cardiovascular system was mainly in the hands of the nervous system and classical hormones called catecholamines (such as epinephrine and norepinephrine). But what if this story is incomplete? Recent research led by pharmacologist Gilberto De Nucci suggests that new mechanisms may be involved. In this article, we explore how the endothelium (the inner lining of blood vessels) produces its own molecules to control blood pressure and heart rate independently of the nervous system.
This article is divided into two parts to make this complex topic easier to understand. In this first part, we revisit what classical physiology said about cardiovascular control. We also explore the first experiments conducted by Prof. De Nucci’s group that led to discoveries challenging classical physiology.
A career marked by groundbreaking discoveries
Professor Gilberto De Nucci’s trajectory is an example of how science advances when someone decides to question what seems established. He earned a degree in Medicine from the University of São Paulo (1981) and in Pharmaceutical Chemistry and Technology from the University of Naples Federico II (2010, Italy). He completed his PhD in Pharmacology at the Royal College of Surgeons of England (University of London, 1986).
Over the years, De Nucci has established himself as one of Brazil’s most influential and productive researchers. Unsurprisingly, he holds full professorship positions at several institutions: State University of Campinas, University of São Paulo, Universidade Brasil, Metropolitan University of Santos, and São Leopoldo Mandic University. In addition, he is a full member of the Brazilian Academy of Sciences, the National Academy of Medicine, the National Academy of Pharmacy, and the Brazilian Association of Translational Cardiology.
Prof. De Nucci built an international and multidisciplinary career. His research spans basic pharmacology (focused on laboratory experiments), clinical pharmacology (focused on effects in humans), and translational pharmacology (focused on transforming discoveries from basic pharmacology into clinical applications). This approach gives even greater relevance to his discoveries, as it directly connects bench experiments with the development of new treatments.
He has made important contributions to different areas of pharmacology and physiology, including cardiovascular physiology, inflammation, and pharmacokinetics (the path a drug takes inside the body). His studies frequently connect different body systems, showing how molecules can act both locally and systemically at the same time.
But more than titles, what defines Prof. De Nucci’s career is the way his investigations approach scientific knowledge: as something always provisional. Science often relies on interpretations that become absolute and unquestioned truths. The researcher’s role is precisely to test these limits.
His challenging stance toward scientific conventions has become even more evident recently. In one of his most provocative lines of investigation, Prof. De Nucci has been discovering that the endothelium is an active source of catecholamines, molecules traditionally associated with the nervous system.
Dear reader, I know I have introduced many words that may be unfamiliar to you, such as “catecholamine” and “endothelium.” But stay with me through the following sections of this article, where everything will make much more sense.
What classical physiology says
Before understanding how the recent discoveries by Prof. De Nucci and his group are revolutionizing everything we know, we need to understand what classical physiology says. Physiology is the branch of science that studies the normal functioning of living organisms. Here, we will focus on cardiovascular physiology, meaning the heart and blood vessels.
Before Prof. De Nucci’s most recent discoveries, cardiovascular function control was explained by a model relatively accepted by the entire scientific and medical community.
Basically, cardiovascular function was believed to be controlled by two major systems: the autonomic nervous system and factors produced by the vascular endothelium. Together, they would be responsible for adjusting blood pressure, vessel diameter, and heart performance (strength and frequency of contractions) in real time.
Let us begin by discussing the autonomic nervous system, and then we will explain the participation of the vascular endothelium. This is because the autonomic nervous system was believed to play the central role in cardiovascular control. It was as if the steering wheel were in its hands, deciding, for example, when the heart should beat faster or slower.
The autonomic nervous system is the part of the nervous system responsible for controlling vital functions that occur automatically, without conscious control. For example, we do not need to think, “heart, increase your beating because I am running from an angry dog.” This differs from when we consciously think, “I will raise my hand.”
It was established that the autonomic nervous system regulated processes such as heart rate, blood pressure, respiration, digestion, and blood vessel diameter, ensuring that the body rapidly adapts to different situations.
The functions controlled by the autonomic nervous system need to be automatic and unconscious because they regulate fundamental aspects necessary for the correct functioning of our body. Imagine if you had to consciously think every time to digest food. What would happen if you forgot?
This system is divided into two main branches: the sympathetic and parasympathetic nervous systems. These names have nothing to do with being sympathetic or pleasant, but rather because these systems “sympathize” with each other. In other words, they act harmoniously and complementarily.
The sympathetic system is activated during fight-or-flight situations, such as danger, physical exercise, or panic attacks. Think about how your body reacts in these situations: your heart beats faster, you sweat more, your mouth becomes dry, and even your lungs seem to expand, allowing you to inhale much more air. All of this results from sympathetic activation.
The parasympathetic system, on the other hand, acts during rest and digest conditions, such as when we are ready to sleep or feel lazy after lunch. The parasympathetic system reduces heart rate, favors digestion, and even makes vision blurrier, preparing the body for a nap.
That is why we say these systems are complementary. They prepare the body for opposite situations, generating opposite responses. For example, while the sympathetic system accelerates the heart, the parasympathetic system slows it down. The balance between these two systems allows body functions to adjust according to the moment’s demands.
How the sympathetic nervous system regulates the heart and blood vessels
Let us dive deeper into cardiovascular control by the sympathetic nervous system, because this is precisely the area revolutionized by Prof. De Nucci’s research.
Within the classical physiology model, the sympathetic nervous system is considered one of the main systems responsible for the rapid adjustment of cardiovascular function. Its action begins with the activation of nerve fibers reaching the heart and blood vessels, releasing molecules called catecholamines from nerve endings.
The classical catecholamines are norepinephrine (the main molecule involved in sympathetic activation), epinephrine, and dopamine. Once released, catecholamines bind to different types of receptors in the heart and blood vessels, triggering several responses. In this case, these receptors are called adrenergic receptors (one of the many receptor groups existing in the body).
In the heart, catecholamines mainly act on β₁ (beta-1) adrenergic receptors, a category of adrenergic receptors. Their binding to these receptors increases heart rate (chronotropic effect) and contraction strength (inotropic effect).
In blood vessels, the effects vary according to the receptor activated. Activation of α (alpha) adrenergic receptors, another category of adrenergic receptors, leads to vasoconstriction (reduction of vessel diameter), increasing blood pressure.
In addition, there are self-regulation mechanisms. Adrenergic receptors located on nerve endings (presynaptic receptors), when activated by catecholamines, can increase (β₂ receptors) or reduce (α₂ receptors) the release of catecholamines themselves from the nerve ending. This works like an intelligent system in which catecholamines regulate their own release to prevent excessive stimulation.
The role of nitric oxide
As mentioned earlier, another important aspect of cardiovascular regulation is nitric oxide production by the endothelium. The endothelium is the layer of cells lining the inside of blood vessels.
Nitric oxide has a set of unique and valuable properties: it is extremely small (composed of only one nitrogen atom and one oxygen atom), electrically neutral, and easily crosses cell membranes. It is as if these properties gave nitric oxide the power to pass through walls inside our body.
Thus, once produced, nitric oxide quickly leaves the endothelium and reaches the vascular smooth muscle. These are basically the muscles that contract to narrow blood vessels (vasoconstriction) or relax to widen them (vasodilation). Nitric oxide relaxes this musculature, leading to vasodilation.
One of the most interesting aspects of nitric oxide is that its production occurs in response to mechanical stimuli. Increased blood flow exerts force on the endothelium, stimulating nitric oxide production. Increased flow may occur, for example, when sympathetic activation causes a vessel to constrict. It is similar to partially blocking the outlet of a hose with your finger: the water flow becomes stronger and faster.
In blood vessels, increased nitric oxide production in response to increased blood flow allows vessels to continuously adjust to the body’s needs: the greater the vasoconstriction, the greater the flow, the greater the nitric oxide release, and the greater the tendency toward vasodilation to counterbalance this effect. In practice, this means that nitric oxide acts opposite to the vasoconstrictor actions of the sympathetic system, helping reduce blood pressure.
The first signs that there was something beyond the nerves
Thus, it was believed that catecholamines were mainly released by nerve endings and that the endothelium played its role primarily through nitric oxide. However, some results began to show that this story was about to gain new chapters.
Everything started when cultures of bovine aortic endothelial cells (the aorta is the body’s main vessel) were shown to produce and release norepinephrine and epinephrine. Until then, it was believed that the endothelium did not produce catecholamines and that they originated exclusively from nerve endings.
Later, Prof. De Nucci’s group obtained surprising results. The group studied the aorta of the corn snake (Pantherophis guttatus). They observed that the aorta contracted in response to electrical stimulation. However, this effect disappeared when adrenergic receptor blockers were added. At first, everything indicated that the catecholamine effects on these receptors were being blocked, preventing vessel contraction.
However, contraction persisted even in the presence of tetrodotoxin. Tetrodotoxin is a toxin derived from pufferfish. It prevents catecholamine release from nerve terminals. If it was blocking this process, then what could still be binding to adrenergic receptors and causing aortic contraction?
Another curious result provided further clues. When researchers removed the endothelium from these vessels, they also lost the ability to contract. Therefore, something coming from the endothelium appeared responsible for vessel contraction.
An especially important result came later. The endothelium of isolated aortas was found to release the classical catecholamines (dopamine, noradrenaline, and adrenaline). For the first time, Prof. De Nucci’s group observed that the endothelium itself is capable of releasing catecholamines, not only sympathetic nerves.
This body of evidence later extended to humans in experiments using umbilical cord vessels. The innovative idea was proposed by researcher Dr. José Britto Júnior. This model is particularly interesting because it lacks innervation. The results showed that the endothelium of these vessels was capable of producing and releasing dopamine.
The new endothelial catecholamines
The idea that the endothelium could produce catecholamines was already gaining strength from experiments in cell cultures and non-innervated vessels. However, some results displayed characteristics that could not be explained by classical catecholamines. There were signs that another, still unidentified molecule might be involved.
Results showed that dopamine produced contraction in umbilical cord vessels. This contraction became greater when nitric oxide production was blocked. As discussed earlier, nitric oxide promotes relaxation. Therefore, it was possible that dopamine’s vasoconstrictor effect was simply being neutralized by nitric oxide’s vasodilatory effect.
It is known that the endothelium continuously produces nitric oxide. Moreover, nitric oxide is highly reactive, interacting with several other molecules in the vascular microenvironment.
At this point, Prof. Edson Antunes, a long-time collaborator of Prof. De Nucci’s group, proposed a hypothesis that would change everything: could catecholamines and nitric oxide interact, since both were being produced by the endothelium?
Indeed, other researchers had already demonstrated that nitric oxide could chemically modify catecholamines, generating so-called nitrated catecholamines. One of the first pieces of evidence emerged at Keio University in studies using rat brains. In that study, researchers observed the presence of a new molecule: 6-nitronoradrenaline, resulting from the association between noradrenaline and nitric oxide.
Based on this hypothesis, Prof. De Nucci’s group decided to investigate the presence of nitrated catecholamines in umbilical cord vessels. They confirmed the presence of 6-nitrodopamine, demonstrating that it was produced by the endothelium.
Already in the first experiments, 6-nitrodopamine showed surprising results. Its effects are opposite to those of dopamine. While dopamine produces vasoconstriction, 6-nitrodopamine produces vasodilation. This explained why dopamine’s vasoconstrictor effects were attenuated when nitric oxide production was blocked. After all, without nitric oxide there is also less transformation of dopamine into 6-nitrodopamine.
Throughout this first part of the article, we have seen how the classical model of cardiovascular physiology is being challenged by unexpected experimental findings from Prof. De Nucci’s group. The endothelium appears not to be merely a passive regulator, but also an active source of catecholamines. More than that, it produces a new catecholamine for the scientific literature: 6-nitrodopamine. These findings suggest that cardiovascular function control is more complex than previously imagined.
In the second part of this article, we will explore what the discovery of 6-nitrodopamine means in practice. You will gain a deeper understanding of the cardiovascular effects of 6-nitrodopamine and learn about the current projects and most recent publications from Prof. Dr. Gilberto De Nucci’s group. We will also discuss the next questions guiding this research. After all, if the endothelium also “speaks” in catecholamines, there is still much to discover about this new language.
The research featured in this article received funding from the São Paulo Research Foundation (grant numbers 11/11828-4, 16/04731-8, 17/15175-1, 18/09765-3, 19/16805-4, 21/13593-6, 21/13726-6, 21/14414-8, 22/07737-8, 22/08232-7, 23/01376-6, 23/04217-6, 23/09792-9, 23/15165-7, and 23/16075-1) and the National Council for Scientific and Technological Development (grant numbers 303839/2019-8 and 140731/2013-0).
This article was produced with support from the São Paulo Research Foundation, Brazil. Grant number 25/17158-3. The opinions, hypotheses, conclusions, and recommendations expressed in this material are the responsibility of the author(s) and do not necessarily reflect the views of FAPESP.
To learn more
Article from Pesquisa FAPESP about the new catecholamines
Guyton & Hall Textbook of Medical Physiology. 14th edition. Rio de Janeiro: Guanabara Koogan, 2021.
Endothelial catecholamines (DOI: 10.1152/physiol.00020.2023)
Written by:
Mia Schezaro Ramos
Pharmacist. Ph.D. in Pharmacology. Science journalist, illustrator, trans, Nintendo enthusiast, K-pop fan, and dependent on physical exercise to stay sane.