The ventrolateral pons plays a key role in the short-term depression (STD) in respiratory frequency following hypoxia; and serotonin, as well as nitric oxide, play a part in the development of long-term facilitation (LTF) following repetitive bouts of hypoxia. GABAa-receptor sub-units in the pontomedullary circuits controlling sympathetic nerve activation (SNA) and phrenic nerve activity (PNA) show differential expression of mRNA following conditioning with hypoxia. Our data indicate that respiratory modulation of SNA not only occurs in a reduced preparation but also quantitatively (increases) and quantitatively changes its activation pattern within a breathing cycle during and following brief periods of hypoxia. Thus, we hypothesize that the up-regulation of SNA results from plasticity in the respiratory neural systems associated with repetitive hypoxic events, a study design called conditioning. To test this hypothesis, we propose a series of neurophysiologic and molecular biologic experiments addressing the following specific aims: 1) to differentiate central versus peripheral mechanisms underlying the increases in SNA following conditioning, 2) to correlate the short-term potentiation and depression (STD) as well as long-term facilitation (LTF) evident in phrenic nerve activity (PNA) with changes in SNA, and 3) to characterize the temporal expression of subunits of GABAa receptors in the brainstem nuclei controlling SNA and PNA in this study design, and 4) to compare the effects of CIH conditioning in two rodent strains with different responses to hypoxia and to nitric oxide synthetase inhibitors. This approach provides an opportunity to determine whether these animals develop increased SNA in proportion to the hypoxic response, and the interrelationship of sympathetic and respiratory control plasticity. These proposed studies examine neurophysiologic and molecular mechanisms relevant to the up-regulation of SNA activity which seems to occur in clinical conditions associated with repetitive hypoxia; e.g., sleep apnea and congestive heart failure.
Showing the most recent 10 out of 339 publications
