The proposed research will continue and extend present investigations into the relationship between the cardiovascular hyperreactivity of the spontaneously hypertensive rat (SHR) to mild alerting stimuli and the etiology of hypertension in this genetic model. Studies are proposed to extend our discovery of a unique, startle-induced heart rate response which identifies a discrete phenotypic difference between SHR and normotensive Wistar-Kyoto (WKY) rats. We have demonstrated that the heart rate trait is inherited in a simple Mendelian fashion and, in the SHR, exhibits genetic linkage to a locus which accounts for over 80% of the hypertension. Further, we have found that the heart rate phenotype involved a central cholinergic pathway which, in response to startle stimuli, activates a parasympathetic response. Studies planned for this grant period will test out thesis that the SHR has a deficient cholinergic activity of this unique, startle-induced pathway. In addition, we seek to define the extent of linkage between the heart rate and hypertension loci, to map these loci using molecular genetics and selected inter-cross breeding between SHR and WKY, to prove or disprove the cholinergic thesis underlying the heart rate phenotype and to identify the brainstem pathways involved. The proposed research identified a totally new direction in efforts to find the hypertension gene(s) in animals an man. In addition, the research proposed should provide new insights into the relationship between environmental stress and cardiovascular disorders, particularly hypertension. Further, the studies directly address the question as to molecular basis of this genetic model of hypertension.
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