Mice with Blunted Hypoxic Ventilatory Response are Susceptible to Respiratory Disturbance during Hypoxia

Abstract

Hypoxia causes a life-threatening situation, and the ventilatory response to hypoxia plays an important role in preventing death. We have hypothesized that persons with a blunted hypoxic ventilatory response may have a weak defense response to hypoxic episodes and be susceptible to fatal respiratory disturbances. However, precise correlations between the hypoxic ventilatory response and respiratory disturbances are not well understood. In the present study we examined the hypoxic and hypercapnic ventilatory responses in nine inbred mouse strains (A/J, AKR/N, BALB/c, C3H/He, C57BL/6, DBA/2, NZW, SWR/J, and 129Sv). Breathing frequency, tidal volume and minute ventilation of unanesthetized and unrestrained mice were assessed by whole body plethysmography. Age-matched mice were exposed for 3 min to 10% O 2 in N 2 gas or 10% CO 2 in hyperoxic gas to determine the acute ventilatory response to chemical stimuli. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the highest in AKR/N mice and the lowest in SWR/J mice. These findings suggest that genetic factors may have influenced the hypoxic ventilatory response but not the hypercapnic ventilatory response. To examine the effects of severe hypoxic stress on the respiratory cycle, we exposed the strain with the highest or lowest hypoxic ventilatory response to 6% O 2 in N 2 until the onset of apnea. The "appearance time of apnea", which is defined as the time from the hypoxic loading to the onset of apnea, was shorter in the SWR/J strain than in the AKR/N strain. We suggest that a lower hypoxic ventilatory response may be a risk factor for apnea under hypoxia.

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“…In contrast, no differences in the hypercapnic ventilatory response were detected (Adachi et al 2006). Interestingly, bw mice showed the augmented responses to either hypoxia or hypercapnea (Takeda et al 2007); the degree of increases was greatest among the nine mouse strains examined (Adachi et al 2006;Takeda et al 2007). Taken together, these results suggest that bw mice are altered in chemosensing probably at the central respiratory controller, including the nucleus tractus solitarius, which represents the first synapse site of the cardiopulmonary reflex afferents (Mizusawa et al 1994;Ogawa et al 1995;Tabata et al 2001).…”

“…AKR/N showed the highest hypoxic ventilatory response, whereas SWR/J showed the lowest responses. In contrast, no differences in the hypercapnic ventilatory response were detected (Adachi et al 2006). Interestingly, bw mice showed the augmented responses to either hypoxia or hypercapnea (Takeda et al 2007); the degree of increases was greatest among the nine mouse strains examined (Adachi et al 2006;Takeda et al 2007).…”

“…We therefore analyzed the ventilation of the bw mice on the C3H/He background (Takeda et al 2007) and the nine inbred mouse strains: A/J, AKR/N, BALB/c, C3H/He, C57BL, DBA/2, NZW, SWR/J, and 129Sv (Adachi et al 2006). We measured breathing frequency, tidal volume and minute ventilation of unanesthetized and unrestrained mice by whole body plethysmography (Mizusawa et al 1994;Ogawa et al 1995;Adachi et al 2004).…”

“…Significant inter-strain variability ( p < 0.05) is indicated by * or † , representing strains with relatively high or low values, respectively. (The data are taken from Adachi et al [2006] and Takeda et al [2007]). tively, we measured the hypoxic and hypercapnic ventilatory responses in bw mice.…”

“…The bw mice and age-matched control mice of each of the nine strains were exposed to 10% O 2 in N 2 gas or 10% CO 2 in hyperoxic gas to determine the acute ventilatory responses to chemical stimuli (Mizusawa et al 1994;Ogawa et al 1995;Adachi et al 2004). Hypoxic ventilatory responses differed among the nine strains; the order of increased minute ventilation was AKR/N > DBA/2 > BALB/c > C3H/He > A/J > C57BL/6 > 129sv > NZW > SWR/J (Adachi et al 2006). AKR/N showed the highest hypoxic ventilatory response, whereas SWR/J showed the lowest responses.…”