Studies are proposed to investigate the cholinergic component of the heart rate response to startle stimuli in the normotensive Wistar-Kyoto rat (WKY) and the basis for the different response of the Spontaneously Hypertensive rat (SHR) model. We propose to correlate previously documented findings on central cholinergic influences on blood pressure with -an analysis of cholinergic agonist and acetylcholinesterase inhibitor elicited neurotransmitter release from tissue minces of selected SHR and WKY brain and spinal regions; an analysis of localization of neurotransmitter controlling enzymes and receptor subtype in the same regions; estimates of the MRNA species encoding enzyme or receptor subtype; and restriction fragment analysis of the gene encoding the receptor or enzyme. Our studies will deal exclusively with regional CNS areas of SHR and WKY rats and will be directed initially to the products of three gene families: (1) the molecular species of acetylcholinesterase, (2) the five muscarinic receptor subtypes, and (3) the CNS nicotinic receptor subunits, alpha2 through alpha4 and beta2 through beta4. Experiments will include extensions of in vivo studies with Unit 1a on the cholinergic component mediating startle-induced bradycardia; a comparison of cholinergic-mediated neurotransmitter release from brainstem and spinal cord preparations from SHR and WKY and potential differential levels of activity of acetylcholinesterase; and radioligand binding of muscarinic and nicotinic subtype receptors in these central nervous system tissues to examine whether a defect involves specific receptors. If differences are found in either receptors or enzyme between SHR and WKY, studies will examine differences in MRNA species encoding a particular receptor subtype and/or differences in receptor expression or gene transcription. Studies will extend into SHRxWKY intercross progeny to determine if observed parental strain differences correlate with phenotype. The proposed investigation should provide a coordinated approach to studying the genetics of the putative cholinergic linkages in genetic hypertension and the associated startle responses.
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