ANGIOTENSIN RECEPTOR FUNCTION IN THE DORSAL MEDULLA

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The objectives are to extend recent findings of interactions with various transmitters (TRs) to determine whether direct or indirect actions of angiotensin peptides mediate the acute CV and baroreceptor effects. Preliminary data suggest that Ang II increases basal release of substance P (SP), but tends to reduce SP release evoked by high potassium. Moreover, others showed that Ang II causes excitation of nodose ganglion neurons, after which a partial depolarization exists. This would tend to reduce responsiveness to a subsequent stimulus. On this basis, my new hypothesis is that Ang II releases SP or norepinephrine (NE) from post- synaptic cells to mediate the acute hypotensive and bradycardic effects. However, Ang II inhibits (or does not facilitate) SP release from vagal afferent fibers when the baroreceptor reflex is activated, leading to attenuation of the baroreceptor reflex. AIM I is to complete the pharmacological profile of the Ang II binding sites in the DMM by determining the Ang receptor subtype(s) mediating release of SP, NE and prostaglandins (PGs) from DMM slices using subtype selective antagonists. These studies are based on our finding of a topographic distribution of DMM receptors with differential sensitivity to AT1 and AT2 competitors. AIM II is to determine whether dose-related CV effects of Ang peptides are linked to release of SP, NE or PGs. Localized injections of relatively specific neurotoxins and pharmacologic antagonists for the above TRs, and synaptic blockade will be used to assess whether the blockade will alter the acute CV responses to microinjections of Ang peptides in the DMM. While the acute CV effects of Ang peptides in the DMM appear to mimic activation of the reflex (hypotensive and bradycardic), Ang II infusions peripherally or centrally inhibit the baroreceptor reflex. Ang II and Ang-(1-7) differentially alter release of SP, NE and PGs, and have opposite effects on the reflex. Thus the opposite effects of Ang II versus Ang-(1-7) on the baroreceptor reflex are a consequence of differential effects on SP, NE, and PGs release. AIM III will determine whether blockade or depletion of the above TR systems alters modulation of the reflex resulting from the Ang peptides. Parallel microdialysis experiments before and during activation of the reflex will verify that release of the particular TRs is modulated by the Ang peptides in a manner consistent with the predicted effects on the reflex.