Many Navy diving operations are performed in cold water. Despite technical advances to improve thermal protection for cold water diving, these applications are cumbersome and do not provide complete thermal protection as thermal discomfort is subjectively reported by many Navy divers. Brown adipose tissue is highly thermogenic in humans. Therefore, activation of brown adipose tissue might improve cold water tolerance and lower thermal discomfort during cold water diving operations. Mirabegron is a beta-3-adrenergic receptor agonist that is used to treat overactive bladder. Beta-3-adrenergic receptors are located on the urinary bladder, gallbladder and brown adipose tissue. Recent evidence has demonstrated that acute mirabegron administration increases thermogenesis for ~3 hours in humans. However, it is currently not known which dose of mirabegron can increase thermogenesis for longer durations. It is also not known if mirabegron administration can improve cold water tolerance and thermal discomfort during cold water immersion. Finally, it is not known if mirabegron can increase thermogenesis during sympathetic stimulation. This project will fill these knowledge gaps by determining if acute mirabegron administration will delay the fall in core temperature and the onset of shivering during a progressive cold-water immersion challenge. This study is part of a collection of studies that will show if mirabegron is a potential ergogenic aid that can be used to improve cold water tolerance in Navy divers which will ultimately improve the likelihood of successful missions.

This is a randomized, double-blind, placebo-controlled, cross-over experimental design. Participants will be asked to complete 3 visits to the laboratory; one informed consent/screening visit and 2 study visits. On study visit days, participants will report to the laboratory following a 12-hour fast, and 24-hour abstention from exercise, caffeine, and alcohol. During the study visits, participants will ingest either a placebo or one dose of mirabegron prior to entering our water immersion tank. Then they will be instrumented for the measurement of heart rate (3-lead ECG), blood pressure (brachial artery auscultation), core temperature (rectal thermistor), and indices of shivering (surface mechanomyography using triaxial accelerometers at 3 anatomic sites (chest, upper back, and thigh), oxygen consumption via ventilation and expired gases, and the bedside shivering assessment scale). Thermal perceptions will be assessed using Likert scales for thermal discomfort and thermal sensation. Following 10 minutes of resting baseline measurements, infrared thermography will then be used to measure skin temperature of the supraclavicular fossa as an estimate of brown adipose tissue activation and thermal perceptions will be assessed.

The measurement of supraclavicular fossa skin temperature (infrared thermography) and thermal perceptions will be assessed every 10 minutes prior to the progressive cold-water challenge. After 30 minutes of seated rest, pre-immersion measurements of heart rate, blood pressure, core temperature, shivering, and thermal perceptions will be conducted and an infrared thermography image will be taken. Then, the water immersion tank will be filled up to the participant's neck with 35 degrees C (95 degrees F) water. Heart rate, blood pressure, core temperature, and shivering indices will be continuously measured. Infrared thermography and thermal perceptions will be obtained every 5 minutes throughout the progressive cold-water challenge. The temperature of the water will be progressively lowered by ~12 degrees C every 60 minutes until the water temperature reaches 10 degrees C (50 degrees F) or until the participant can no longer tolerate the cold or if rectal temperature reaches 35.5 degrees C (95.9 degrees F). Upon completion of the progressive cold water challenge, the water in the tank will be rapidly emptied. Participants will gently towel dry and will be able to don a circulating warm water perfused suit and/or use a mylar blanket to reestablish core temperature.

Participants will be asked to return to the laboratory after 10-14 days to repeat the experiment with the drug assignment not yet received. Each participant's order of assignment to placebo or drug ingestion (prior to the cold water challenge) over the 2 study visits will be randomly assigned.

Inclusion Criteria:

• Men and women
• 18-40 years old
• Participate in 150 minutes or more of at least moderate intensity exercise per week during the previous 2 years

Exclusion Criteria:

• diagnosed autonomic disease
• diagnosed cardiovascular disease
• diagnosed metabolic disease
• diagnosed neurologic disease
• diagnosed endocrine disease
• diagnosed respiratory disease
• diagnosed liver dysfunction
• diagnosed kidney dysfunction
• Women who are pregnant or breastfeeding
• Individuals currently taking a medication (with the exception of birth control, including hormonal contraception) that cannot be safely discontinued for 5 biological half-lifes prior to each study visit based on consultation with the study physician.
• Current tobacco or electronic cigarette use or consistent use within the last 1 year

Adverse event data were collected for each subject after informed consent was obtained and up to their study completion (up to 6 months).