Genetic determinants of acute hypoxic ventilation: patterns of inheritancein mice

Acutely lowering ambient O-2 tension increases ventilation in many mammalia n species, including humans and mice. Inheritance patterns among kinships a nd between mouse strains suggest that a robust genetic influence determines individual hypoxic ventilatory responses (HVR). Here, we tested specific g enetic hypotheses to describe the inheritance patterns of HVR phenotypes am ong two inbred mouse strains and their segregant and nonsegregant progeny. Using whole body plethysmography, we assessed the magnitude and pattern of ventilation in C3H/HeJ (C3) and C57BL/6J (B6) progenitor strains at baselin e and during acute (3-5 min) hypoxic [mild hypercapnic hypoxia, inspired O- 2 fraction (FIO2) = 0.10] and normoxic (mild hypercapnic normoxia, FIO2 = 0 .21) inspirate challenges in mild hypercapnia (inspired CO2-fraction = 0.03 ). First- and second-filial generations and two backeross progeny were also studied to assess response distributions of HVR phenotypes relative to the parental strains. Although the minute ventilation (VE) during hypoxia was comparable between the parental strains, breathing frequency (f) and tidal volume were significantly different; C3 mice demonstrated a slow, deep HVR relative to a rapid, shallow phenotype of B6 mice. The HVR profile in B6C3F (1)/J mice suggested that this offspring class represented a third phenotyp e, distinguishable from the parental strains. The distribution of HVR among backcross and intercross offspring suggested that the inheritance patterns for f and VE during mild hypercapnic hypoxia are consistent with models th at incorporate two genetic determinants. These results further suggest that the quantitative genetic expression of alleles derived from C3 and B6 pare ntal strains interact to significantly attenuate individual HVR in the firs t- and second-filial generations. In conclusion, the genetic control of HVR in this model was shown to exhibit a relatively simple genetic basis in te rms of respiratory timing characteristics.