Acute adjustments in ventilation represent a powerful homeostatic mechanism for the maintenance of P02, PC02 and pH. Sensory feedback to the ventilatory control centers occurs via peripheral and central chemoreceptors, but here are several unresolved questions regarding the roles and relative importance of central chemoreceptors and their contributions to blood gas regulation during eupneic ventilation, and putative interactions peripheral chemoreceptors and central chemoreceptors. The overall goal of this proposal are to address questions regarding chemoreception by taking advantage of unique inbred rat strains with inherent, and large differences in C02 sensitivity;the Brown Norway (BN: low responder) and Dahl Salt-sensitive (SS: high responder) rat. First, I will determine if the deficit in C02 sensitivity in BN rats is due to decreased cellular C02/pH sensitivity of individual chemosensitive neurons in vitro, or numbers and/or altered morphology of chemosensitive neurons via immunohistochemistry. The hypothesis that central chemoreceptors play little role .in the regulation of eupneic PC02 and pH will be tested in the second aim by characterizing the effects of carotid body denervation in these strains. Last, there is evidence that the carotid chemoreceptors may directly regulate central C02 sensitivity. In the third aim, I will test this possibility using a combined in vivo and in vitro approach by first measuring the ventilatory response to focal acidosis in chemosensitive regions in adult BN and SS rats, and then by quantifying the cellular C02/pH sensitivity of individual central chemoreceptor neurons in vitro in BN and SS neonates before and after carotid body denervation. Applying these experimental techniques to these unique rat strains will provide significant insights into the relative roles and importance of peripheral and central chemoreception in eupneic ventilation, and their putative interaction. They will also provide insights into respiratory-related diseases, and will provide a framework for future genomic investigations aimed at identifying the genetic determinants, and therefore the unique cellular mechanisms by which central chemoreception occurs.
