In the latest article from the Farmaco em Foco blog, we showed how the discovery of catecholamines produced by the vascular endothelium began to challenge one of the most classical concepts in physiology. Now, a new publication led by researchers from the University of Campinas further deepens this conceptual revolution and reveals the main physiological effects of these “new catecholamines” in different organs of the body.
The study has just been published (May 2026) in the British Journal of Pharmacology, one of the world’s most traditional and influential journals in the field of pharmacology. The article was authored by four professors from the Graduate Program in Pharmacology at Unicamp: Prof. Mariana Gonçalves de Oliveira, Prof. Edson Antunes, Prof. Fabiola Zakia Monica, and Prof. Gilberto De Nucci.
The article brings together all the evidence accumulated over recent years regarding the so-called new catecholamines, especially 6-nitrodopamine and 6-cyanodopamine. The publication shows how these molecules directly participate in cardiovascular regulation, penile erection, ejaculation, and urinary and respiratory tract function.
In this Farmaco em Foco article, we will explain the main actions of the new catecholamines described in the publication. Farmaco em Foco also interviewed the main scientist behind these discoveries: Prof. Gilberto De Nucci.
The Endothelium Stopped Being Just a “Lining” Long Ago
The discovery that the endothelium is capable of producing and releasing its own catecholamines goes far beyond contradicting what classical physiology proposed. This finding helps explain phenomena that were still mysterious.
One such case involves transplanted organs. After transplantation, organs lose their original innervation. Nevertheless, they maintain their physiological functions. For example, the heart rate of a transplanted heart still increases when a person exercises, such as during running. Classical physiology would argue that this effect occurs through stimulation by sympathetic nerves. But how would this be possible if the transplanted heart is no longer innervated?
This is why it makes so much sense that the endothelium can release catecholamines capable of producing these effects in transplanted organs independently of innervation. Everything began with the discovery of endothelial 6-nitrodopamine, but the story was only beginning.
6-Cyanodopamine: Poison or Physiological Molecule?
If the discovery of 6-nitrodopamine already seemed to challenge physiology textbooks, the later identification of 6-cyanodopamine pushed this story even further.
6-Cyanodopamine was identified in the cardiac endothelium of rats and rabbits, as well as in the vas deferens (the tube of the male reproductive system responsible for transporting sperm from the testicles to the urethra during ejaculation) of rats and humans, in addition to human circulation.
The most intriguing aspect of this molecule is that it contains a cyanide group. Cyanide is historically associated with toxic effects and is widely known as a poison. Cyanide prevents cells from using oxygen to produce energy. As a result, vital organs such as the brain and heart rapidly stop functioning, leading to death.
However, recent studies suggest that small amounts of cyanide-related compounds may naturally exist in the body. The importance of these molecules for physiological function remains poorly understood. Perhaps 6-cyanodopamine is the key to answering this question.
Vascular Effects: Where It All Began
The first effects investigated were the vascular actions of 6-nitrodopamine. Studies show that the molecule acts extremely powerfully on vascular smooth muscle.
In experimental models, 6-nitrodopamine promoted intense vascular relaxation. This effect is more potent than that produced by the classical vasodilator acetylcholine (a mediator of the parasympathetic nervous system discussed in part 1 of this article). In other words, much less 6-nitrodopamine is required than acetylcholine to produce the same vascular relaxation.
Even more surprising is that these effects appear to occur through mechanisms different from the traditional nitric oxide pathway, which is unexpected since 6-nitrodopamine derives from the interaction between nitric oxide and dopamine.
Nitric oxide-mediated vasodilation has been considered the main mechanism responsible for vascular relaxation for decades. Discovering that 6-nitrodopamine can act through an entirely different pathway to produce the same effect revolutionizes physiology and opens possibilities for new therapeutic targets.
Besides relaxing blood vessels, 6-nitrodopamine also strongly regulates dopamine-induced vascular responses. In experiments, 6-nitrodopamine reduced dopamine-induced contraction without interfering with the actions of the other classical catecholamines (noradrenaline and adrenaline).
In other words, the classical catecholamines (dopamine, noradrenaline, and adrenaline) cause vascular contraction. Until now, any molecule capable of blocking this effect (antagonists) failed to distinguish between the classical catecholamines. That is, antagonists blocked contractions produced by all catecholamines. 6-Nitrodopamine is the first selective antagonist for dopamine-induced vascular contraction.
This finding is extremely relevant. When we discover a highly selective molecule, it creates the potential for better treatments. The more selective a drug is, the fewer unwanted side effects it tends to produce, because it acts only where it is supposed to act.
For example, tricyclic antidepressants such as Amitriptyline treat depression by acting on serotonin and noradrenaline pathways in the brain. However, they are poorly selective and also interfere with catecholamine and acetylcholine pathways in other parts of the body. These additional effects lead to side effects such as dry mouth, constipation, and ejaculatory dysfunction.
The Heart Also Produces Catecholamines
The new catecholamines also demonstrated remarkable effects on the heart. According to the studies reviewed by the researchers, the cardiac endothelium (also called the endocardium) produces 6-nitrodopamine and 6-cyanodopamine.
Experiments showed that these substances increase heart rate and cardiac contractile force. These effects are traditionally associated with adrenaline and noradrenaline.
Just as observed in blood vessels, 6-nitrodopamine also potentiates the effects of classical catecholamines in the heart. Extremely small amounts of 6-nitrodopamine were able to amplify the actions of dopamine, noradrenaline, and adrenaline on the heart.
The Epithelium Has Entered the Catecholamine Map
Just as the endothelium forms the inner lining of blood vessels and the heart, the epithelium lines other organs such as the urinary tract and respiratory airways. New studies from Prof. Gilberto De Nucci’s group suggest that, like the endothelium, the epithelium may also produce and release catecholamines such as 6-nitrodopamine and 6-cyanodopamine.
This discovery was made in the epithelium of genitourinary structures such as the seminal vesicles, vas deferens, ureter, and bladder.
Local Control of Erection and Ejaculation
Studies involving the new catecholamines revealed particularly important effects in reproductive and urinary organs. 6-Nitrodopamine and 6-cyanodopamine were shown to act directly on the smooth muscle of these organs while also modulating the effects of classical catecholamines.
The corpus cavernosum is the tissue responsible for penile erection. In this tissue, 6-nitrodopamine promotes potent smooth muscle relaxation. This step is essential for increasing blood flow, which is indispensable for erection.
It is similar to a party balloon: if the balloon’s latex is soft and elastic (like a relaxed muscle), it is easier to fill it with air. If the balloon is stiff, no matter how hard you blow, you will not be able to inflate it. Something similar occurs during erection, except that the penis fills with blood rather than air.
The new catecholamines also appear to be important for the function of the seminal vesicles and vas deferens, structures essential for ejaculation. Rather than producing strong contractions on their own, 6-nitrodopamine and 6-cyanodopamine act synergistically to greatly amplify contractions induced by classical catecholamines.
These contractions are essential for pushing semen components toward the urethra, leading to ejaculation, functioning like a type of “muscular pumping” mechanism.
Interestingly, tricyclic antidepressants were also found to reduce the effects of 6-nitrodopamine. These antidepressants are known to cause ejaculatory dysfunction, although these effects are still poorly understood. Perhaps we failed to understand these effects until now simply because the new catecholamines had not yet been discovered.
Regulation of the Urinary Tract
In addition to the reproductive system, researchers detected the release of these catecholamines by the ureter (the tubes that carry urine from the kidneys to the bladder) and the bladder, both fundamental structures for urinary flow regulation.
In the human ureter, 6-nitrodopamine produces contractions, although weaker than those induced by classical catecholamines. These contractions are important for ureteral peristalsis, the coordinated contractile movement responsible for pushing urine from the kidneys to the bladder.
Once again, 6-nitrodopamine demonstrated the ability to potentiate the effects of classical catecholamines. The molecule appears to function as a local modulator of neural stimuli. This may become important in situations such as the passage of kidney stones through the ureter. This process could mechanically stimulate the epithelium, causing it to produce more 6-nitrodopamine and further increasing the contractions necessary to expel the stone.
This finding may become relevant for the treatment of renal colic. Currently, medications used to facilitate stone elimination (alpha-adrenergic blockers) can cause side effects such as dizziness and hypotension. If selective drugs targeting the actions of 6-nitrodopamine can eventually be developed, they may represent safer therapeutic alternatives.
A New Hypothesis for Bladder Dysfunction
In the urinary bladder, the results also challenged traditional concepts. Studies showed that 6-nitrodopamine strongly relaxes bladder smooth muscle and reduces contractions induced by acetylcholine, a molecule fundamental for bladder emptying. In other words, 6-nitrodopamine makes urine elimination more difficult.
Animals deficient in nitric oxide production exhibit important urinary alterations, such as increased urinary frequency and impaired relaxation of bladder smooth muscle.
Traditionally, these problems were attributed solely to nitric oxide deficiency. However, the new findings suggest that at least part of these alterations may result from the loss of 6-nitrodopamine production that occurs when nitric oxide levels are reduced.
This hypothesis is important because it may change how certain urinary dysfunctions are interpreted. If confirmed by future studies, this idea could open the door to new therapeutic approaches, since current treatment options remain poorly effective.
Interview with Prof. Gilberto De Nucci
Farmaco em Foco spoke with Prof. Gilberto De Nucci. Between stories of rejected papers, international collaborations, and future plans, the researcher also reflected on the role of scientists.
Why do you think it took so long for someone to investigate these new catecholamines?
“I suspect it’s because the paradigm has always been that catecholamines are associated with the autonomic nervous system. In the case of dopamine, as a mediator of the central nervous system. So, this idea of catecholamines being released by the endothelium and epithelium, playing roles in the peripheral body, was relegated to the background.”
Have you encountered resistance from the scientific community in accepting your discoveries?
“Look, we encountered much more resistance in the beginning. We had several papers rejected immediately. Including for reasons that left me extremely surprised. One editor told us: ‘If you are correct, everything we teach in physiology is wrong. So we are going to reject the paper.’
About two or three years ago, we submitted a paper on 6-nitrodopamine in rabbit corpus cavernosum. All three reviewers rejected it, but none of them criticized the experiments. They simply said the concept was absurd. In other words, they did not request additional experiments. They did not criticize any experiment that had been performed. They just said it made no sense. That nitric oxide was the main mediator. We eventually published the study in Andrology.
We also had other papers rejected. The first paper on 6-cyanodopamine in the vas deferens was submitted to the European Journal of Pharmacology. The editor rejected it, saying it was not a pharmacological study. I think that was because it involved 6-cyanodopamine. It was the first pharmacological study involving a cyanide-containing mediator, and it was rejected immediately. Eventually, we published it in a German journal, the European Journal of Physiology.
There is an interesting historical detail. That journal is quite old. While reading a 19th-century science book, I came across Eduard Friedrich. He was a German physiologist and founder of the journal. He was the first scientist to propose cyanide as having a role in the biogenesis of life. I do not know whether the editor knew this or whether it was a historical coincidence, but I found it very interesting. Especially since it was the first journal to accept a pharmacology paper involving the first cyanide-containing mediator ever described in biology.
The first international conference where I presented the new catecholamines was in Denmark, in 2021. My presentation focused on 6-nitrodopamine, but at the end of the conference I showed data on the release of 6-cyanodopamine. I remember a medicinal chemistry professor standing up and saying: ‘Cyanide is a poison, this is absurd.’
I think the situation is better now. Both because the British Journal of Pharmacology invited us to write a review, and because the review we published in the Journal of Physiology became one of the journal’s most cited reviews, according to the journal itself. Now, at least, papers are no longer being rejected immediately.”
Are you now seeing several groups investigating these molecules as well?
“There are several groups abroad with whom we have collaborated. I have postdoctoral researchers and PhD students working overseas. For example, the paper published this year, carried out in London with Prof. Albert Ferro, demonstrates the action of 6-nitrodopamine in smooth muscle cells. It is the first study performed in cell culture.
There is another group in the United States that is very enthusiastic. Prof. Ruhul Abid’s group, where postdoctoral researcher Dr. Bruna Lourençoni Alves is working with human femoral veins. They are very interested in the action of 6-nitrodopamine in human coronary endothelial cells.
Here in Brazil, several groups have also started collaborating with us based on the results we have been publishing.
There is also the example of a group completely independent from ours: Prof. Masato Tsutsui’s group in Okinawa, Japan. He provided the triple nitric oxide synthase knockout mouse that we have been using in the laboratory. Now he is interested in studying these new catecholamines in the context of cancer.”
Do you believe these discoveries could have direct impacts on medicine and lead to new therapies?
“I believe there is unexplored potential in the central nervous system. We also have a collaborative study, which has not yet been published, with Prof. Soraia Katia Pereira Costa at USP. It is based on our previous work showing that tricyclic antidepressants block dopamine action in certain peripheral tissues. She observed that the analgesic effects of these antidepressants may actually result from blocking 6-nitrodopamine.
We already have a reasonable number of studies on 6-nitrodopamine, and so far nobody else has become interested in investigating 6-nitrodopamine in depression within the central nervous system. I remember that about two years ago there was a Gordon Conference in the United States focused on dopamine. I wanted to participate. I sent an email and they never even replied.
Because it’s difficult. A discovery made in a third-world country, without any foreign authors. And it’s not just one discovery. It’s not only about 6-nitrodopamine itself, but also 6-cyanodopamine. It is a highly revolutionary concept, especially cyanide acting as a biological mediator.
But this resistance is decreasing. And because of that, I think the pharmaceutical industry, which is essential for developing new drugs, will eventually become interested.
I remember that when I used to buy 6-nitrodopamine from Toronto Research Chemicals, they sold it in 100-milligram packages. Now it comes in 1-gram bottles. So more people are buying it.
And we are now starting to collaborate more with groups working directly with humans. With that, we will have a greater possibility of eventually verifying its physiopathological role.”
Are there any other physiological roles you hope to investigate in the future?
“I do not work directly with the central or peripheral nervous system. My work is more focused on the cardiovascular system and other systems, such as the genitourinary system. I believe there are still important roles to be understood in these systems.
This identification of 6-nitrodopamine as a selective dopamine receptor antagonist, without affecting adrenergic receptors, is, in my opinion, a very important concept because all the antagonists we currently have are not selective.
So, I believe that just as the classical catecholamines act in several systems, these new catecholamines should also have effects in multiple systems.
Another important issue is that, so far, we only know the new catecholamines themselves, but we still do not know their metabolites or how they are metabolized. So I think we now need to invest in this area.
We also have an unpublished study involving a beetroot juice that is very popular in England. It is famous for its high nitrate content. We measured it and observed that this juice contains large amounts of dopamine and noradrenaline. What surprised me most was that we also found 6-nitrodopamine and 6-nitronoradrenaline. So you can see that these catecholamines are quite ancient.”
Besides 6-nitro- and 6-cyanodopamine, in some of your studies you mention the possibility of other catecholamines, such as 6-bromodopamine. What would be the relevance of these molecules?
“We published a paper involving 6-bromodopamine. It was found circulating in patients with renal failure. We have not yet published it, but we also have evidence for other catecholamines.”
Was there ever a moment when your data seemed too good to be true?
“Well, with 6-cyanodopamine I felt somewhat uncomfortable. I began my work with 6-nitrodopamine. A Japanese group had already demonstrated the formation of 6-nitronoradrenaline. Even though they had not demonstrated the release of 6-nitrodopamine, it still seemed plausible.
A chemistry professor from the United States contacted me before the pandemic saying she had other dopamine analogues and asking whether I wanted to work with them. At the time, I considered using 6-cyanodopamine as an internal standard. I did not suspect it was an endogenous molecule. But just to be safe, I asked for endogenous 6-cyanodopamine levels to be measured.
When we found it, I became extremely uncomfortable. I was very hesitant. I only published after I found reports in the literature showing that humans have circulating cyanide levels.
I ended up publishing the results in an analytical journal. This is a strategy I use for publishing these new mediators, because people in those journals mainly analyze the analytical methodology itself, without considering the biological impact. Then it becomes easier to overcome resistance later, because when you approach a pharmacology journal, you have already demonstrated that the methodology has been completely validated.”
What would you like young researchers to learn from your scientific journey?
“Believe in the data you obtain. Sometimes students say, ‘the experiment didn’t work.’ Not working is complicated. perhaps it simply did not produce the result you expected.
I remember my mentor, Dr. John Vane, who won the Nobel Prize in Physiology or Medicine in 1982. He discovered prostacyclin in 1976. One day he showed me some papers from the 1960s and said: ‘prostacyclin was already here, I just didn’t see it.’
So I think it is important to trust your results, even if they go against what everyone else is saying.
I make a distinction between a researcher and a scientist. A researcher does research; a scientist does science. Many people perform studies simply to confirm what is already in the literature. Science is about breaking paradigms, not just confirming them.As my other mentor, Dr. Sérgio Henrique Ferreira, used to say: ‘Science is about opening windows. And to open windows, you have to break walls.’”
The studies presented in this article were supported by FAPESP (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, 23/13692-0, 23/15165-7, 23/16075-1, 24/08982-1, 24/12679-2, 24/12688-1, 24/13160-0, 24/14880-7, 24/16759-0, 24/17989-0, 24/20567-0, 24/20651-0, 25/00804-0, 25/00926-8, 25/01272-1, 25/11569-1 and 25/19466-7) and CNPq (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:
New review published in the British Journal of Pharmacology (DOI: 10.1111/bph.70503)
6-Nitrodopamine in vascular smooth muscle cell culture (DOI: 10.1111/bcpt.70224)
Cardiovascular effects of the new catecholamines in fish (DOI: 10.1016/j.cbpa.2026.111991)
6-Nitrodopamine in rattlesnake vessels (DOI: 10.1242/jeb.251103)
6-Nitrodopamine in the human ureter (DOI: 10.1111/bph.70324)
6-Cyanodopamine in the human vas deferens (DOI: 10.1016/j.ejphar.2025.178315)
6-Nitrodopamine in seminal vesicles (DOI: 10.1002/prp2.70167)
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.