The principal aim of this proposal is to determine the effects of hypertension on synthesis of atrial and brain natriuretic peptides (ANP and BNP) by neurons and glia of the cerebral cortex. Although originally discovered in the cardiac atria where it is secreted as a peripheral hormone with natriuretic, diuretic and vasorelaxant properties, ANP has also been found in the brain where it functions as a neurotransmitter/neuromodulator in neural pathways subserving cardiovascular regulation and fluid/electrolyte balance, BNP, a recently discovered neuropeptide, is structurally and functionally similar to ANP but has a different distribution in the brain. In preliminary studies, two cell type in the neocortex, large pyramidal neurons and astroglia, were found to be intensely immunoreactive for ANP. Since other studies have reported hypertension-associated increases in cortical ANP, this study will determine whether these particular cell types are being stimulated to increase ANP/BNP synthesis. These findings will be of particular interest since both cell types have apparent intimate relationships with cerebral blood vessels. Therefore, release of ANP/BNP by either cell type might play a role in regulation of cerebral blood flow. To this end, the densities of ANP- and BNP-positive neurons and glia in the neocortices of normotensive and hypertension will be determined by immunohistochemical staining and the contents of ANP and BNP in various regions of the neocortex will be determined by radioimmunoassay. In addition, the location and degree of transcription of ANP mRNA will be determined by hybridization with a labelled cDNA probe, both in solution and in situ. Several different methods of inducing hypertension will be used to determine if the effects are model-dependent. Also, the ultrastructural relationships of ANP/BNP-immunopositive neurons and glia to blood vessels will be investigated by electron microscopy. Finally, astroglia will be cultured to more directly investigate their role in synthesizing and/or binding ANP/BNP. Elevated cerebral arterial pressure produces several effects in the brain including altered hemodynamics, vascular damage and breakdown of the blood-brain barrier all of which are common to various cerebrovascular diseases, including stroke. Understanding of the functions of neuronal and glial ANP/BNP systems in regulation of local or regional blood flow and fluid/electrolyte homeostasis at the blood-brain barrier, as well as the opportunities for manipulation of these systems, would be of great significance in the prevention and treatment of stroke and other diseases such as cerebral edema and hydrocephalus.
| McKenzie, J C; Juan, Y W; Thomas, C R et al. (2001) Atrial natriuretic peptide-like immunoreactivity in neurons and astrocytes of human cerebellum and inferior olivary complex. J Histochem Cytochem 49:1453-67 |
| McKenzie, J C; Berman, N E; Thomas, C R et al. (1994) Atrial natriuretic peptide-like (ANP-LIR) and ANP prohormone immunoreactive astrocytes and neurons of human cerebral cortex. Glia 12:228-43 |
| McKenzie, J C; Kelley, K B; Merisko-Liversidge, E M et al. (1994) Developmental pattern of ventricular atrial natriuretic peptide (ANP) expression in chronically hypoxic rats as an indicator of the hypertrophic process. J Mol Cell Cardiol 26:753-67 |
| McKenzie, J C (1992) Atrial natriuretic peptide-like immunoreactivity in astrocytes of parenchyma and glia limitans of the canine brain. J Histochem Cytochem 40:1211-22 |
