The long range goal of this research is to determine the role of neurotransmitter metabolism in the regulation of breathing. The research proposed has been divided into two sections.
Aim 1 : To determine the effects that alterations in acide-base status (produced by varying the amount of CO2 in the inspired gas mixture with or without hypoxia) have on the levels and turnovers of nerepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytrytamine or 5HT) within four specific subdivisions of the CNS--brain stem, hypothalamus, striatum, and hemispheres (remainder)--and in the carotid bodies (CB). An average--of a) the rate of monoamine buildup after inhibition of the degradative enzyme monoamine oxidase, and of b) the rate of monoamine breakdown after inhibition of tyrosine and tryptophan hydroxylation, the rate-limiting biosynthetic step--will be the index of monoamine turnover.
Aim 2 : To determine the relationships between neurochemical metabolism and rat ventilation. This section will rely on the use of awake, unrestrained rats (with and without carotid bodies) prepared with chronically indwelling femoral artery catheters to obtain arterial blood gas and acid-base measurements. Hyperventilation will be indicated by a drop in PaCO2 and hypoventilation will be shown by an elevated PaCO2. Alteration of endogenous catecholomines [by using tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMT) and other pharmacologic manipulations] in rats without carotid bodies will clarify the status of CNS catecholamine mediated ventilatory effects. The specifics of the catecholamine mediated effects will be clarified in an awake goat model. We have previously shown that depletion of endogenous 5HT produces hyperventilation (presumably through a CNS 5HT mechanism which normally inhibits ventilation). However, a) administration of serotonin precursor, 5-hydroxytrytamine (5HTP), or b) intracerebroventricular (ICV) injection of 5HT can either produce hyper- or hypo- ventilation depending on pharmacologic and physiologic (anesthesia) state. We plan to analyze CNS 5HT and its (potentially active) metabolic products to determine a correlation between the ventilatory response and the status of 5HT in the CNS. The results of these studies will provide basic knowledge applicable to clinical respiratory care in a broad sense ranging from anesthesiology, neonatology, and the care of chronic respiratory disease.
