Influence of chronic hypoxia on the hypoxic ventilatory response of juvenile and adult rats

Abstract

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition - from blunting to augmenting the HVR - occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O₂) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 - 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one "typical" pattern for VAH in adult rats.

Keywords: Acclimation; Control of breathing; Hypoxia; Rat substrain; Respiratory plasticity; Ventilatory acclimatization to hypoxia.

Fig. 1.

Hypoxic ventilatory response of juvenile rats (Crl:SD) exposed to 21% O₂ (Control) or 12% O₂ (CH) for approximately one week. (A) P21–22 rats were exposed for 7–8 days beginning at P14 (Control: n= 10 females, 15 males; CH: n= 17 females, 19 males). (B) P28–29 rats were exposed for 7 days beginning at P21 or P22 (Control: n= 10 females, 16 males; CH: 9 females, 18 males). Ventilation (mean±SEM) was measured in 21% O₂ and again after 20 min in 12% O₂. * P≤0.05 vs. Control at the same inspired O₂ level.

Fig. 2.

Hypoxic ventilatory response of adult, male rats (Crl:SD) after 3 days and 7 days in 21% O₂ (Control; n= 11) or 12% O₂ (CH; n= 13). Ventilation (mean±SEM) is reported under baseline (BL; 21% O₂) conditions and throughout a 20-min exposure to 12% O₂ after 3 days and 7 days (panels A and B, respectively). In panel C, the final two time points during hypoxia were averaged. * P≤0.05 vs. Control at the same time point.

Fig. 3.

Hypoxic ventilatory response of adult, male rats (Hsd:SD) after 3 days and 7 days in 21% O₂ (Control; n= 12) or 12% O₂ (CH; n= 11). Ventilation (mean±SEM) was measured in 21% O₂ and then in 12% O₂. * P≤0.05 vs. Control at the same inspired O₂ level.

Fig. 4.

Hypoxic ventilatory response of adult rats (Crl:SD) after 14 days in 21% O₂ (Control) or 12% O₂ (CH). Ventilation (mean±SEM) was measured in 21% O₂ and then in 12% O₂. Sample sizes (n) were Control: 10 females, 7 males and CH: 7 females, 10 males.

Fig. 5.

Hypoxic ventilatory response of adult, male rats (Crl:SD) after 7 days in 21% O₂ (Control; n= 9) or 12% O₂ (CH; n= 10). To determine whether the order of the test gases influences the magnitude of the ventilatory response, ventilation (mean±SEM) was measured in 12% O₂ before 21% O₂ for CH rats; Control rats were presented with 21% O₂ before 12% O₂. * P≤0.05 vs. Control at the same inspired O₂ level.

Fig. 6.

Metabolic responses to hypoxia of adult rats (Crl:SD) after 7 days in in 21% O₂ (Control) or 12% O₂ (CH). (A) O₂ consumption, (B) CO₂ production, and (C) the respiratory exchange ratio (RER) were measured in 21% O₂ and again after 20 min in 12% O₂; values are mean±SEM. * P≤0.05 vs. Control across both inspired O₂ levels (i.e., main effect for treatment group).

Fig. 7.

Hypercapnic ventilatory response of adult rats (Crl:SD) after 7 days in 21% O₂ (Control) or 12% O₂ (CH). Ventilation (mean±SEM) was measured in 0% CO₂ (21% O₂, balance N₂) and then in 7% CO₂ (21% O₂, balance N₂). Sample sizes (n) were Control: 9 females, 7 males and CH: 6 females, 9 males. * P≤0.05 vs. Control across both inspired CO₂ levels (i.e., main effect for treatment group).

Fig. 8.

Hypoxic ventilatory response of adult, male rats (Crl:SD) after 7 days in 21% O₂ (Control; n= 13) or 10% O₂ (CH; n= 12). Ventilation (mean±SEM) was measured in 21% O₂, 12% O₂, and 10% O₂. * P≤0.05 vs. Control at the same inspired O₂ level.

Fig. 9.

Patterns of ventilatory acclimatization of hypoxia (VAH) observed in the literature for adult rats. (A) Patterns were characterized based on whether normoxic ventilation (NX), hypoxic ventilation (HX), or the change in ventilation (HVR) differed between CH and Control groups; CH was considered to have had an effect if the difference between groups exceeded 10% (i.e., ratios greater than or equal to 1.1, or ratios less than or equal to 0.9). The three principal patterns included no change in the acute HVR (pattern 1), an augmented HVR (pattern 2), or a blunted HVR (pattern 3); pattern 3 was subdivided based on whether hypoxic ventilation was increased compared to chronically hypoxic rats (pattern 3A), unchanged (pattern 3B), or decreased (pattern 3C). (B) Relative frequency for patterns of VAH in adult rats based on the 25 published studies (including the present study) for which sufficient data were available (see Appendix B). (C) Data from panel B separated based on whether normobaric hypoxia (Normo; n= 9.25 studies) or hypobaric hypoxia (Hypo; n= 15.75 studies) was used for the CH exposure. Individual published studies were used as the unit of replication, so fractions of studies were counted where multiple relevant data sets were reported in the same study (see Methods section for details).