Hypoxic ventilatory response during light and dark periods and the involvement of histamine H1 receptor in mice

Abstract

Ventilation oscillates throughout a day in parallel with oscillations in metabolic rate. Histamine affects ventilation and the balance of the energy metabolism via H1 receptors in the brain. We tested the hypothesis that the ventilatory response to hypoxia varies between light and dark periods and that histamine H1 receptors are required for the circadian variation, using wild-type (WT) and histamine H1 receptor knockout (H1RKO) mice. Mice were exposed to hypoxic gas (7% O(2) + 3% CO(2) in N(2)) during light and dark periods. Ventilation initially increased and then declined. In WT mice, minute ventilation (.Ve) during hypoxia was higher in the dark period than in the light period, which was an upward shift along with the baseline ventilation. Hypoxia decreased the metabolic rate, whereas O2 consumption (.VO(2)) and CO(2) excretion were higher in the dark period than in the light period. However, in H1RKO mice, changes in Ve during hypoxia between light and dark periods were minimal, because .Ve was increased relative to .VO(2), particularly in the light period. In H1RKO mice, the HCO(3)(-) concentration and base excess values were increased in arterial blood, and the level of ketone bodies was increased in the serum, indicating that metabolic acidosis occurred. Respiratory compensation takes part in the .Ve increase relative to .VO(2) during hypoxia. These results suggested that changes in .Ve during hypoxia vary between light and dark periods and that H1 receptors play a role in circadian variation in .Ve through control of the acid-base status and metabolism in mice.

Time-Dependent Ventilatory Response to Poikilocapnic Hypoxia during Light and Dark Periods and the Role of Histamine H1 Receptors in Mice

“…These circadian variations can be caused by neural inputs from the circadian pacemaker located in the suprachiasmatic nuclei, or by indirect influences on ventilatory control via the circadian rhythms of other variables [3]. Recently, the ventilatory response to hypoxia was also found to vary between light and dark periods in mice [4].…”

“…In earlier studies, we observed biphasic ventilatory responses to normocapnic hypoxia in mice. We added 3% CO 2 to the hypoxic gas to maintain a constant level of arterial PCO 2 (PaCO 2 ) [2,4,7]; this prevents hypocapnia induced by hypoxic hyperventilation [8]. Indeed, our previous blood gas analyses in mice showed PaCO 2 levels of 36-39 mmHg at 10 min after 7% O 2 inhalation adding 3% CO 2 [4, 9], but 19 mmHg at the same time after 7% O 2 inhalation [10].…”

“…We focused on the ventilatory responses to poikilocapnic hypoxia in which the PaCO 2 level decreased over time, and compared these responses to those of normocapnic hypoxia. Circadian variation has also been observed in ventilatory response to normocapnic hypoxia [4], but ventilatory responses to poikilocapnic hypoxia remain unknown.…”

“…These circadian variations can be caused by neural inputs from the circadian pacemaker located in the suprachiasmatic nuclei, or by indirect influences on ventilatory control via the circadian rhythms of other variables [3]. Recently, the ventilatory response to hypoxia was also found to vary between light and dark periods in mice [4].Hypoxic gas inhalation causes time-dependent ventilatory responses under limited oxygen availability [5]. These responses involve an initial increase based on peripheral chemoreceptor afferents activated by hypoxia and a subsequent decline accompanied by a decrease of the metabolic rate.…”

“…We focused on the ventilatory responses to poikilocapnic hypoxia in which the PaCO 2 level decreased over time, and compared these responses to those of normocapnic hypoxia. Circadian variation has also been observed in ventilatory response to normocapnic hypoxia [4], but ventilatory responses to poikilocapnic hypoxia remain unknown.Histamine H1 receptors in the brain are involved in hypoxic ventilatory control, specifically the HVD accompanying decrease in the metabolic rate [7]. Histamine is known as a functional neuromodulator that tonically acts on the respiratory neuron network and is further activated during hypoxia [14].…”