The Exercise and Environmental Physiology Lab at the University of Oregon has a healthy stock of treadmills and heart and breathing rate monitors — and antihistamines. The drugs aren’t there to help the researchers combat the spring pollen season in Eugene, but rather to help them understand the role histamine plays in exercise. 

Since unexpectedly linking histamine to exercise, human physiologist John Halliwill has been captivated by how a signaling molecule associated with allergies regulates responses to physical activity. Using human trials and transcriptomic analysis, Halliwill explores histamine’s influence on beneficial exercise adaptations spanning energy metabolism, blood flow, and inflammation, the physiological triggers and molecular mechanisms underlying these relationships, and the differences between exercise-induced histamine signaling and allergic reactions. By mapping the complex pathways histamine paves in the body, Halliwill hopes to guide the use of antihistamine drugs to treat allergies without interfering with its positive exercise based effects. 

How did you become interested in studying the role of histamine in exercise? 

As a doctoral student, I started researching postexercise hypotension, which is a period of reduced blood pressure that the majority of people experience after a single bout of exercise. It makes some individuals more susceptible to fainting immediately after exercise. While working through the mechanisms of why blood pressure drops after exercise, we realized that there's something released in the system when we exercise that dilates blood vessels and reduces blood pressure, and it's not one of the things we conventionally think about for blood pressure regulation. Eventually, out of curiosity and frustration, we made a laundry list of everything we could think of that could dilate blood vessels, and histamine made the list. Fortunately, we looked at histamine sooner rather than later because there are so many good drugs that we could use to block it in our human studies. 

How do you investigate the role of histamine in exercise?

Most of my research focuses on understanding the pathways involved in the underlying physiology by using pharmacological interventions to block either the histamine H1 or H2 receptor, which both seem to be involved in the response to exercise. We use doses that are higher than the typical over the counter doses to achieve a more significant blockade of these receptors to better see the impact on the physiology. 

In a standard experiment, someone performs a type of aerobic or endurance exercise. We measure a physiological variable such as blood pressure or blood flow to the exercising muscle groups. We then block the histamine receptors and look at the outcome variables. 

What have you learned about the role of histamine in exercise?

We have some contradictory information about the role of histamine in blood flow during exercise that may arise from the limits of our measurements. We can monitor blood flow in large blood vessels that distribute blood to exercising muscles, such as the femoral artery, using vascular ultrasound. When we studied recovery from exercise, we found that blood flow had increased, but if we gave histamine blockers in advance of exercise, that didn’t happen (1). 

When we measured blood flow during exercise, it increased in proportion to exercise intensity. But when we gave histamine blockers, instead of seeing a decrease in blood flow as we had anticipated, we saw a slight increase in peripheral artery blood flow. That left us scratching our heads. 

At the same time, we conducted a competitive time trial in cyclists in which we gave them histamine blockers or placebo drugs (2). The cyclists given the histamine blockers performed worse and took longer to complete the time trial. Their muscles probably weren’t getting as much blood with the histamine blockers, even though the ultrasound measurements showed that blood flow was actually higher. My hypothesis is that when we give the histamine blockers during exercise, we alter blood flow distribution within the skeletal muscle and impair perfusion of the more active areas. The blood flow at the femoral artery looks elevated, but the blood doesn’t reach the locations needed to support exercise.

When we studied recovery from exercise, we found that histamine released in the skeletal muscle can help deliver glucose by increasing blood flow and likely by enhancing the permeability of the capillaries so that glucose more readily accesses the skeletal muscle. In some individuals, histamine blockers reduced muscle glucose uptake during recovery from exercise, but it wasn't consistent (3). 

Another research group at Ghent University found that blocking histamine receptors impaired higher glucose processing, an adaptation we normally associate with exercise training (4). This provides some evidence that histamine is a molecular transducer that drives some of the adaptations to exercise training, including vascular and metabolic effects.

What is the goal of your current human study? 

When we exercise, histamine is released and acts as a molecular signal, activating a cascade of events that lead to some of the adaptations to exercise training. We're trying to pin down the exact role of histamine. Is it simply modulating some of these responses, or is it a major driver behind them? 

One of our current projects investigates why exercise makes the skeletal muscle release histamine and what is the upstream signaling in that pathway. There's a lot going on within the skeletal muscle tissue during exercise: changes in temperature, oxygen, carbon dioxide, pH, electrolytes, metabolites, and physical stressors (5). We’re once again creating a laundry list of all the things that change and might influence histamine and its release in the skeletal muscle.

What have you discovered about the cellular targets of histamine?

What really amazed me when we started looking at the transcriptome data was how widespread an influence the histamine blockade had (6). There are H1 and H2 receptors on vascular endothelial cells, vascular smooth muscle cells, and likely other cells within the skeletal muscle tissue. But skeletal muscle cells make up the bulk of the skeletal muscle tissue, and to the best of our knowledge, they don't have H1 and H2 receptors. When we look at the transcription factors that directly influence transcription, they don’t bind histamine. 

What is histamine doing to broadly influence the transcriptome? Some signals we saw were like night and day. If we blocked histamine receptors, we saw no change in transcription. But if we didn’t, we saw a robust response from exercise. Other times, the histamine blockade modulated transcription rather than completely shutting it off. So, we have to consider if changes in muscle blood flow and shear stress alter the transcriptome response, or if changes in glucose delivery affect the metabolic state of the cells to influence transcription. There are a lot of simple stories about how a cell signaling molecule leads to turning a gene on or off. But it’s a complicated, messy story with histamine, and that's how it influences so many things.  

How does histamine release during exercise differ from that of an allergic reaction?

It’s like the line about real estate: location, location, location. Where histamine is released has a huge influence on how it affects the system. When we exercise, skeletal muscles release histamine, and it alters blood flow and capillary permeability in that tissue. Under different circumstances, histamine released in the lining of the nasal passages increases blood flow and capillary permeability there, causing a stuffy, runny nose. 

Beyond that, the triggers for histamine release are likely different. Mast cells, immune cells that reside in multiple different tissue types, are one of the most common sources of histamine. When we exercise, mast cells in the skeletal muscle tissue release histamine, but we haven't figured out what the trigger is. Mast cells in the skin or mucous membranes are commonly involved in true allergic reactions where an antigen binds to an antibody and interacts with a mast cell surface receptor. We don’t think what we observe during exercise has that same sort of origin; there's no antigen involved. We think it's either a chemical signal released from the skeletal muscle or some aspect of the microenvironment within the skeletal muscle.

What are the implications of your research for drug development and human health?

An overwhelming number of the diseases in the Western world — high blood pressure, obesity,  cardiovascular disease — can be improved by exercise, and histamine plays an important role in that. If I could develop one magic drug, it would turn on histamine receptors where we want them turned on and not throughout the whole body where it could lead to allergy symptoms. But if we could turn them on in the skeletal muscle and elicit some of these positive adaptations we see with exercise training, that could offer health benefits. In the absence of that magic drug, though, what we've got is exercise.

I’m interested in understanding what advice I can give individuals to treat their allergies without undermining the benefits of histamine when they exercise. I'm really excited about over the counter inhaled H1 blockers. If someone’s primary problem is a runny nose from seasonal allergies, instead of taking an oral H1 blocker that blocks the histamine receptors throughout his or her whole body that may undermine some of those positive responses to exercise, he or she can use a nasal spray to target the H1 receptors at the source of their symptoms. 

This interview has been condensed and edited for clarity. 

References

1. Halliwill, JR, Buck, TM, Lacewell, AN & Romero, SA. Postexercise hypotension and sustained postexercise vasodilation: What happens after we exercise? Exp Physiol  98, 7–18 (2013).  
2. Ely, MR et al. Histamine-receptor antagonists slow 10-km cycling performance in competitive cyclists. Med Sci Sports Exerc  51, 1487–1497 (2019).
3. Emhoff, CA, Barrett-O’Keefe, Z, Padgett, RC, Hawn, JA, & Halliwill, JR. Histamine-receptor blockade reduces blood flow but not muscle glucose uptake during postexercise recovery in humans. Exp Physiol  96, 664–673 (2011).  
4. Van der Stede, T et al. Histamine H₁ and H₂ receptors are essential transducers of the integrative exercise training response in humans. Sci Adv  7, eabf2856 (2021). 
5. Mangum, JE et al. The effect of local passive heating on skeletal muscle histamine concentration: implications for exercise-induced histamine release. J Appl Physiol  132, 367-374 (2022). 
6. Luttrell, MJ & Halliwill, JR. The intriguing role of histamine in exercise responses. Exerc Sport Sci Rev  45, 16–23 (2017).