Depression Of Respiratory Frequency Research Articles

The kreisler mutation leads to the loss of intrinsically hypoxia-activated spots in the region of the retrotrapezoid nucleus/parafacial respiratory group

Acute hypoxia elicits a biphasic respiratory response characterized in the newborn by a transient hyperventilation followed by a severe decrease in respiratory drive known as hypoxic respiratory depression. Medullary O(2) chemosensitivity is known to contribute to respiratory depression induced by hypoxia, although precise involvement of cell populations remains to be determined. Having a thorough knowledge of these populations is of relevance because perturbations in the respiratory response to hypoxia may participate in respiratory diseases in newborns. We aimed to analyze the hypoxic response of ponto-medullary cell populations of kreisler mutant mice. These mice have defects in a gene expressed in two rhombomeres encompassing a part of the medulla oblongata implicated in hypoxic respiratory depression. Central responses to hypoxia were analyzed in newborn mice by measuring respiratory rhythm in ex vivo caudal pons-medullary-spinal cord preparations and c-fos expression in wild-type and kreisler mutants. The homozygous kreisler mutation, which eliminates most of rhombomere 5 and mis-specifies rhombomere 6, abolished (1) an early decrease in respiratory frequency within 10 min of hypoxia and (2) an intrinsic hypoxic activation, which is characterized by an increase in c-fos expression in the region of the ventral medullary surface encompassing the retrotrapezoid nucleus/parafacial respiratory group expressing Phox2b. This increase in c-fos expression persisted in wild-type Phox2b-negative and Phox2b-positive cells after blockade of synaptic transmission and rhythmogenesis by a low [Ca(2+)](0). Another central response was retained in homozygous kreisler mutant mice; it was distinguished by (1) a delayed (10-30 min) depression of respiratory frequency and (2) a downregulation of c-fos expression in the ventrolateral reticular nucleus of the medulla, the nucleus of the solitary tract, and the area of the A5 region. Thus, two types of ponto-medullary cell groups, with distinct anatomical locations, participate in central hypoxic respiratory depression in newborns.

Age-dependent involvement of ATP-sensitive potassium channel Kir6.2 in hypoxic ventilatory depression of mouse

In order to examine whether ATP-sensitive potassium channel Kir6.2 is involved in hypoxic ventilatory responses, especially in hypoxic ventilatory depression (HVD), and whether the involvement shows age-dependence, we measured the hypoxic ventilatory response in the Kir6.2-knockout mouse (Kir6.2-/-) in an unanesthetized unrestrained state by means of pressure plethysmography in the 2nd and 4th postnatal weeks, and compared the response with that of its wild type counterpart, the C57BL6/J mouse. In the 4th postnatal week, but not in the 2nd week, the Kir6.2-/- exhibited a larger and longer initial augmentation and a weaker subsequent depression of respiratory frequency and ventilation in response to hypoxia (FIO(2)=0.12 in N(2)). These findings suggest that Kir6.2 is involved in HVD of the mouse at a certain point during the postnatal development.

Effect of 2,4-dinitrophenol under non-oxygenated condition in pons–medulla–spinal cord preparations in newborn rats: Comparison with medulla–spinal cord preparations

We tested whether depression of respiratory frequency (fR) under non-oxygenated artificial cerebrospinal fluid (aCSF) in pons–medulla–spinal cord (PMS) and medulla–spinal cord (MS) preparations is significantly influenced by the mitochondrial uncoupler 2,4-dinitrophenol (2,4-DNP) in newborn rats.Preparations were obtained from 0- to 4-day-old rats, and fR was monitored at the C4 ventral root in environmental temperature (24 °C). 2,4-DNP was dissolved in aCSF (1, 10 or 30 μM; pH 7.4), and we measured fR in PMS ( n = 19) and MS ( n = 16), both of which were superfused with aCSF equilibrated with oxygenated (95% O 2–5% CO 2) or non-oxygenated (10% O 2–5% CO 2, balanced with pure N 2) gas.Our results showed that: (1) fR was significantly lower in PMS than MS, (2) fR was significantly decreased under non-oxygenated aCSF in both PMS and MS and (3) fR under non-oxygenated aCSF was significantly increased by 2,4-DNP applications at 10 and 30 μM in PMS but not in MS.Our results suggest that depression in fR under non-oxygenated aCSF in PMS and MS may not be due simply to O 2 limitation, and 2,4-DNP has a stimulant effect on the medullary respiratory rhythm generator (RRG) through pontine RRG regulatory mechanisms under non-oxygenated aCSF.