NTS Purinoreceptor in Integrative Cardiovascular Control

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DESCRIPTION (Applicant's abstract): The nucleus tractus solitarius (NTS) is a major integrative site in the dorsal medulla for processing viscerosensory information involved in cardiovascular control and reflex coordination of regionally distinct autonomic response patterns. The NTS contains a rich vocabulary of neurotransmitters/neuromodulators mediating and modulating NTS integration among which both adenosine and ATP have been strongly implicated in the control of autonomic nerve activity and hence control of cardiovascular function. Adenosine levels within the NTS vary with both physiological and pathophysiological states (e.g., ischemia, hypotensive hemorrhage, high gravitational stress). Recent studies strongly support the concept that adenosine, acting via adenosine P1 purinoceptors, plays a neuromodulatory role in the mechanisms of autonomic control by the NTS. In addition, several lines of evidence from our laboratory and by others have suggested that ATP, acting at P2x purinoceptors, serves as a fast transmitter substance in NTS-mediated mechanisms of baroreflex control of the peripheral circulation. Nearly all previous studies regarding the actions of adenosine and ATP were restricted to either the effects at the cellular level or to observing only global cardiovascular responses (e.g., changes in arterial pressure and heart rate). Inasmuch as cardiovascular control is a highly integrative process and demonstrates marked regional variability in both physiological and pathophysiological settings, our laboratory has combined the powerful approaches of microinjection of very small quantities of substances into discrete brainstem areas with sophisticated peripheral cardiovascular instrumentation capable of monitoring regional vascular and efferent neural activities to develop a unique animal model to investigate the mechanisms of modulation of cardiovascular control by the NTS utilizing "state-of-the-art" methodologies and analytical techniques. Studies described in this proposal are focused on determining the functional importance and efferent mechanisms whereby adenosine and ATP act within the NTS to mediate and modify integrative control of the cardiovascular system. These studies will significantly increase our understanding of the functional importance of processes identified at the cellular level in the integrative coordination of cardiovascular control mechanisms and may aid in the development of new pharmacological approaches to the treatment of altered central neural control of cardiovascular function.