Histamine Modulation for Low Blood Pressure

Overseen By John R Halliwill, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Oregon

Must not be taking: Antihistamines

Disqualifiers: Cardiovascular disease, Diabetes, Asthma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to examine how histamine affects the body's ability to adapt to exercise, particularly in individuals with naturally low blood pressure. It involves various types of exercise, such as aerobic (steady cardio) and heating (warming the body), to observe changes in blood and muscle. The trial seeks participants with low blood pressure who do not have major health issues like heart disease or diabetes. As an Early Phase 1 trial, this research focuses on understanding histamine's effects in people, offering participants the chance to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

The trial requires that participants are not on any ongoing medical therapy, except for birth control, and do not use over-the-counter or prescription antihistamines.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that aerobic and resistance exercises are generally safe and manageable for most people. These exercises can help lower blood pressure and improve heart health. For instance, moderate aerobic exercise can reduce blood pressure by up to 8.9 mmHg. Resistance training is also safe for individuals with or without heart problems.

Regarding heat therapy, studies suggest it is well-tolerated. People who have tried it often report no negative effects. In one study, participants experienced no issues even when using heat therapy overnight.

Overall, these findings suggest that the treatments under study, such as aerobic exercise, resistance exercise, and heat therapy, have a good safety record. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments because they explore innovative ways to manage low blood pressure through physical interventions rather than medications. Traditional treatments often rely on dietary adjustments, increased fluid and salt intake, or medications like fludrocortisone and midodrine. However, these experimental approaches aim to enhance blood pressure by boosting blood flow and muscle perfusion through aerobic exercise and heating. This could offer a non-drug alternative, minimizing side effects and potentially improving overall cardiovascular health. By measuring blood and muscle responses, researchers hope to uncover new insights into how physical activities can naturally stabilize blood pressure.

What evidence suggests that this trial's treatments could be effective for low blood pressure?

Research has shown that both aerobic exercises, such as walking or cycling, and resistance exercises, like weightlifting, can help lower blood pressure. In this trial, participants will be assigned to different treatment arms to evaluate these effects. One arm will focus on aerobic exercise, which studies have found can reduce the systolic blood pressure by about 14 points. Another arm will involve heating, while resistance training, previously studied in a now-closed arm, also helps lower both systolic and diastolic blood pressure, especially for people over 60. This evidence suggests that combining both types of exercise may benefit heart health and help manage blood pressure. ^{1 3 6 7 8}

Who Is on the Research Team?

John R Halliwill, PhD

Principal Investigator

University of Oregon

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 18-40 who have not been diagnosed with cardiovascular disease, diabetes, autonomic disorders, or asthma. Participants should not smoke or use nicotine and must not be on any antihistamines or ongoing medical therapy (except birth control). They cannot be pregnant, breastfeeding, planning pregnancy soon, highly active physically, overweight (BMI over 28), non-English speaking, or have high blood pressure.

Exclusion Criteria

You have a high level of physical activity based on the International Physical Activity Questionnaire.

I am currently on medication other than birth control.

You are allergic to certain drugs, anesthetics, skin disinfectants, adhesives, or latex.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Exercise Intervention

Participants perform exercise or participate in interventions like heating to study histamine's role in adaptation to exercise

1 hour per session

Multiple sessions (in-person)

Follow-up

Participants are monitored for histamine concentration and metabolites in blood and urine

24 hours

What Are the Treatments Tested in This Trial?

Interventions

• Exercise

Trial Overview The study examines how histamine helps the body adapt to exercise by comparing the effects of aerobic exercise alone versus combined resistance and aerobic exercise. It also tests the impact of blocking histamine with a drug called alpha-FMH and using common antihistamines after exercising.

How Is the Trial Designed?

Group I: Resistance and Aerobic Exercise Experimental Treatment 1 Intervention

Blood and urine collected during recovery from two modalities of exercise (This arm is now CLOSED)

Group II: Heating Experimental Treatment 1 Intervention

Blood and skeletal muscle microdialysate collected during local and/or whole body heating

Group III: Aerobic Exercise and Muscle Perfusion Experimental Treatment 2 Interventions

Muscle perfusion measured during aerobic exercise (This arm is now CLOSED)

Group IV: Aerobic Exercise Experimental Treatment 1 Intervention

Blood and skeletal muscle microdialysate collected during dynamic knee-extension exercise

Who Is Running the Clinical Trial?

University of Oregon

Lead Sponsor

Trials

91

Recruited

46,700+

Published Research Related to This Trial

In a study involving 16 volunteers, taking combined histamine H1/H2-receptor antagonists during exercise led to increased leg blood flow, contrary to the expectation that blocking histamine would reduce it.

The increase in blood flow was observed across various exercise intensities (20% to 80% of peak power) and during prolonged exercise, suggesting that histamine may play a complex role in regulating blood flow during physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of histamine-receptor antagonism on leg blood flow during exercise. Ely, MR., Ratchford, SM., La Salle, DT., et al.[2021]

In a study of 49 young and healthy individuals (22 Black and 27 Caucasian), it was found that Black participants exhibited elevated diastolic blood pressure (BP) after exercise, unlike Caucasians, indicating different cardiovascular responses to exercise between these groups.

The study suggests that histamine receptors (H1R and H2R) may play a role in these differential responses, as their blockade affected stroke volume differently in Black and Caucasian participants, highlighting potential implications for cardiovascular disease risk in Black individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Post-Exercise Blood Pressure Responses between Blacks and Caucasians. Yan, H., Behun, MA., Cook, MD., et al.[2022]

A single session of aerobic exercise leads to a drop in blood pressure (postexercise hypotension) and prolonged widening of blood vessels (vasodilatation) in the muscles that were exercised, which is influenced by reduced sympathetic nerve activity and local vasodilator mechanisms.

Recent studies suggest that specific receptors in the brain and histamine receptors in muscles are crucial for these postexercise effects, indicating potential therapeutic avenues for managing conditions like hypertension and diabetes through exercise recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postexercise hypotension and sustained postexercise vasodilatation: what happens after we exercise? Halliwill, JR., Buck, TM., Lacewell, AN., et al.[2022]

In a study of 20 recreationally active males, those with high-normal blood pressure exhibited an exaggerated blood pressure response to exercise, which was linked to impaired histamine receptor function.

The blockade of histamine H1 and H2 receptors during exercise led to increased mean arterial pressure and decreased total vascular conductance in normotensive individuals, suggesting that histamine plays a role in regulating blood pressure responses during physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of combined histamine H1 and H2 receptor blockade on hemodynamic responses to dynamic exercise in males with high-normal blood pressure. Naylor, A., Shariffi, B., Gillum, TL., et al.[2021]

In a study of 14 healthy men, histamine was found to lower blood pressure and vascular resistance during submaximal exercise by activating H2 receptors, indicating its role in cardiovascular regulation during physical activity.

The blockade of H2 receptors led to increased blood pressure and cardiac workload during exercise, suggesting that histamine's effects are primarily vascular rather than affecting the heart muscle directly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histamine H2 receptor blockade augments blood pressure responses to acute submaximal exercise in males. Doh, HW., Stebbins, CL., Choi, HM., et al.[2017]

After small muscle-mass dynamic exercise, there is a significant increase in blood flow to the exercised leg, which is mediated by histamine receptors, as shown in a study involving 21 participants.

In contrast, resistance exercise does not lead to sustained vasodilatation, indicating that the mechanisms activating histamine receptors are specific to the type of exercise performed, particularly aerobic activities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained postexercise vasodilatation and histamine receptor activation following small muscle-mass exercise in humans. Barrett-O'Keefe, Z., Kaplon, RE., Halliwill, JR.[2022]

During and after acute aerobic exercise, interstitial histamine levels in skeletal muscle increase, which is crucial for sustaining blood flow to active muscles, with a significant increase of 4.2 ng/ml observed post-exercise.

The increase in histamine is due to both the de novo formation via the enzyme histidine decarboxylase and mast cell degranulation, indicating that exercise triggers a response that enhances muscle recovery and blood flow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mast cell degranulation and de novo histamine formation contribute to sustained postexercise vasodilation in humans. Romero, SA., McCord, JL., Ely, MR., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11699555/

Differential Effects of the Type of Physical Exercise on Blood ... Among persons aged ≥65 years, muscle strength training programs appear to be more effective in inducing exercise-related positive changes in BP ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0167494324004126

Differential effects of exercise training protocols on blood ... The findings indicated that performing 30 min of aerobic exercise per week significantly decreased both SBP and DBP. However, other systematic reviews and meta- ...

3. frontiersin.org frontiersin.org/journals/public-health/articles/10.3389/fpubh.2025.1548584/full

Aerobic activity significantly reduces blood pressure ... Pooled results showed the effectiveness of the aerobic activity intervention in lowering blood pressure, with a − 14.03 mmHg reduction in SBP ...

4. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.18099

Acute Aerobic Exercise Induces Short-Term Reductions in ... A single bout of acute aerobic exercise, reduces ambulatory BP over 24 hours in medicated and nonmedicated hypertensive adults.

5. bjsm.bmj.com bjsm.bmj.com/content/57/20/1317

Exercise training and resting blood pressure: a large-scale ... Overall, isometric exercise training is the most effective mode in reducing both systolic and diastolic blood pressure. These findings provide a comprehensive ...

6. ahajournals.org ahajournals.org/doi/10.1161/CIR.0000000000001189

Resistance Exercise Training in Individuals With and ... Resistance training is a safe and effective approach for improving cardiovascular health in adults with and without cardiovascular disease.

7. heart.org heart.org/en/healthy-living/fitness/fitness-basics/aha-recs-for-physical-activity-in-adults

AHA Physical Activity Recommendations ... Recommendations for Adults. Get at least 150 minutes per week of moderate-intensity aerobic activity or 75 minutes per week of vigorous aerobic ...

8. escardio.org escardio.org/Councils/Council-for-Cardiology-Practice-(CCP)/Cardiopractice/physical-activity-for-cardiovascular-prevention

Physical activity for cardiovascular prevention Engaging in physical activity (PA) and maintaining adequate cardiorespiratory fitness is associated with health advantages for all individuals.