The effect of hypothalamic temperature setpoint inhibition at a central and peripheral level on exertional elevations of core body temperature.

Core body temperature (CBT) is normally strictly regulated by the body*s
natural thermostat, localized in the hypothalamus. This thermostat compares the
measured core body temperature with the hypothalamic temperature setpoint,
which is set between 36.0 * 37.5°C in physiological situations. If the CBT
becomes too high, the hypothalamus initiates several adaptational mechanisms
(e.g. peripheral vasodilatation, sweating and behaviour adaptations) in order
to pass on the excess heat to the environment, allowing the CBT to return to
its normal values. Physical exercise almost always results in an elevated CBT,
and current concepts state that this is solely the result of metabolic heat
production due to muscle labour whilst the temperature setpoint remains
unchanged. Another (non-exertional) mechanism that leads to an elevated CBT is
the elevation of the hypothalamic temperature setpoint itself. Several
processes are activated by this mechanism, resulting in an increased CBT. An
elevated hypothalamic temperature setpoint is typically caused by
pro-inflammatory cytokines such as IL-1* or IL-6 which are released during
infection or inflammation. These cytokines stimulate the enzyme cyclo-oxygenase
(COX) to produce the mediator prostaglandin E2 (PGE2), and it is this mediator
that increases the temperature setpoint in the hypothalamus. The most important
antipyretic medications act through inhibition of COX on a central level
(paracetamol/acetaminophen) or peripherally (NSAIDs). Whilst it is postulated
that the CBT rise during physical exercise is solely the result of metabolic
heat production, it has also been described that several pro-inflammatory
cytokines are released during exercise. It is therefore also possible that the
hypothalamic setpoint becomes elevated during exercise, and this would partly
explain the CBT rise if this is indeed the case. Gaining a better insight into
this mechanism is important, since a better understanding of thermoregulation
during exercise could lead to new points of action in the prevention of
hyperthermia and could hence also lead to better prevention of heat-related
disorders. Recently, a few studies were published that substantiate that an
altered temperature setpoint during exercise may play a role, however these
studies were methodologically limited by inhibiting COX at only one level. In
the present study, we want to test the hypothesis that the CBT rise during
exercise is partly due to an elevated hypothalamic temperature setpoint. We
will test this hypothesis by inhibiting PGE2 synthesis at both a central and a
peripheral level in healthy subjects, after which they will perform submaximal
treadmill exercise for 60 minutes whilst CBT will be continuously measured. By
blocking PGE2 synthesis at both a central and a peripheral level, we will
surpass the methodological limitations of previous studies that inhibited PGE2
synthesis at only a single level. In addition to inhibiting COX centrally and
peripherally, we will also inhibit PGE2 synthesis as a third condition in order
to compare our findings with previous studies.

To determine changes in core body temperature under simultaneous inhibition of
prostaglandin E2 synthesis at a central and peripheral level (paracetamol +
ibuprofen) compared to a control condition (no inhibition of PGE2 synthesis)
and with inhibition of PGE2 synthesis at only a central level (paracetamol)
during 60 minutes of submaximal treadmill exercise.

Randomised controlled trial with crossover design.

Subjects will all perform submaximal treadmill exercise. Before every exercise
test, one of the following interventions will be applied in random order 45
minutes prior to the start of exercise:
A: Central and peripheral COX-inhibition: Paracetamol 1000mg dissolved in 100mL
water + ibuprofen 400mg dissolved in 100mL water.
B: Central COX-inhibition: Paracetamol 1000mg dissolved in 100mL water + 100mL
water (as control for ibuprofen).
C: No COX-inhibition: Two times 100mL water (control for paracetamol and
ibuprofen).

Maximal exercise tests are safe and are not associated with substantial health
risks. A potential risk of maximal exercise tests is the development of an
acute coronary syndrome. In subjects of 40 years and younger, sudden cardiac
death is mainly ascribed to congenital cardiac disorders, whilst in subjects
older than 40 years sudden cardiac death is mainly ascribed to cardiovascular
disease. It should be emphasized that these potential complications are rare.
Submaximal exercise tests are also safe and are not associated with substantial
health risks. Moreover, this type of exercise is performed by millions of
recreational athletes without the occurrence of (serious) health problems. The
potential risks of submaximal exercise tests are similar to those of maximal
exercise tests, however the risk is lower due to the submaximal aspect of these
tests. All test locations are equipped with an emergency kit containing
emergency medication. This kit is compiled and checked by the institutional
pharmacy of the Radboudumc. Furthermore, an Automatic External Defibrillator
(AED) is present at all test locations. Furthermore, a venipuncture will be
performed at a total of 6 time points throughout the study in order to draw a
blood sample in which IL-1* and IL-6 will assessed. A complication that may
occur after a venipuncture is the occurrence of a haematoma. This haematoma is
self-limiting and will heal without any significant health risks.