Central blockade of nitric oxide transmission impairs exercise-induced neuronal activation in the PVN and reduces physical performance

Abstract

The blockade of central nitric oxide (NO) signaling modifies the thermoregulatory and metabolic adjustments that occur during exercise, thereby impairing physical performance. However, the brain areas involved in this response remain unknown. Nitrergic neurons are present in the hypothalamic areas that are activated during exercise and participate in autonomic and neuroendocrine responses, such as, the hypothalamic paraventricular nucleus (PVN) and the supraoptic nucleus (SON). To investigate whether brain NO signaling affects thermoregulation during exercise through the activation of hypothalamic neurons, rats underwent acute submaximal treadmill exercise (18 mmin(-1), 5% inclination) until fatigue received an intracerebroventricular injection of 1.43 μmol Nω-nitro-l-arginine metil ester (L-NAME), a nitric oxide synthase inhibitor, or saline (SAL). Skin tail temperature (Tsk) and internal body temperature (Ti) were continuously recorded and c-Fos expression was determined in the PVN and the SON. L-NAME treatment reduced physical performance by 48%, which was positively correlated with tail vasodilation capacity, which was reduced by 28%, and negatively correlated with heat storage rate (HSR), which was increased by 38%. Physical exercise until fatigue increased the number of c-Fos-immunoreactive (ir) neurons in the PVN and the SON. L-NAME-treatment significantly reduced the exercise-induced c-Fos expression in the PVN, whereas it had no effect in the SON. Interestingly, the number of c-Fos-ir neurons in the PVN was closely correlated with physical performance and inversely associated with HSR. Thus, the inhibition of central NO attenuates neuronal activation induced by exercise in the PVN, impairs the autonomic regulation of heat dissipation, and anticipates the fatigue. Brain NO seems to play a role in exercise performance through the regulation of neuronal activation in the PVN, but not in the SON, although the SON neurons are also activated by running exercise. Moreover, this role in performance mediated by neuronal activation in the PVN can be related with the improvement of thermoregulatory adjustments that occur during exercise.

Pre-exercise exposure to the treadmill setup changes the cardiovascular and thermoregulatory responses induced by subsequent treadmill running in rats

“…46 In contrast, the effect of restraint stress on both the corticosterone concentrations and c-fos expression was much smaller in rats restrained once daily for 4 days and nonexistent in rats restrained once daily for 9 days. 46 In the present study, our rats were familiarized via running on a treadmill for 5 days, which is the traditional protocol employed in our lab 18,19,33 and by other research groups 23,47,48 ; even fewer familiarization sessions have been employed by other groups, e.g., 3 days 44 or 4 days. 15 These habituation protocols were designed to minimize the exposure of rats to the electrical stimuli and improve the running pattern during experimental trials.…”

The improvement of exercise performance by physical training is related to increased hypothalamic neuronal activation

“…Whether the training‐mediated changes in the sympathetic reflex for cutaneous heat loss are associated with adaptation within the central nervous system is still unknown. This hypothesis is reinforced by evidence that situations of hyperthermia activate several nuclei in the brain . During exposure to a hot environment or acute exercise, thermosensitive neurons are activated in thermoregulatory centres such as the preoptic area and the paraventricular nucleus of the hypothalamus (PVN) .…”

“…This hypothesis is reinforced by evidence that situations of hyperthermia activate several nuclei in the brain . During exposure to a hot environment or acute exercise, thermosensitive neurons are activated in thermoregulatory centres such as the preoptic area and the paraventricular nucleus of the hypothalamus (PVN) . The preoptic area plays a key role in the control of thermoregulatory adjustment .…”

Nitrate supplementation improves physical performance specifically in non-athletes during prolonged open-ended tests: a systematic review and meta-analysis

“…Increased NO availability resulting from NO 3 − supplementation has beneficial effects on health and physical performance and has been largely studied in humans and laboratory animals. In the central nervous system, NO prevented exaggerated increases in the core body temperature in rats subjected to exercise by increasing cutaneous heat loss and decreasing the metabolic cost of running (10)(11)(12)(13) . In these rat studies, the pharmacological blockade of central NO synthesis markedly impaired endurance (10,12) , whereas an increased NO availability in the brain did not affect endurance (13) .…”