Recent studies suggest that altered central dopaminergic (DA) activity contributes to the development of hypertension. The goal of the present research is to test the hypothesis that central DA neurons contribute to cardiovascular control in the normotensive rat and that functional alterations in these neurons are involved in the pathogenesis of hypertension in the spontaneously hypertensive rat of the Okamoto strain (SHR) and the DOCA/NaCl hypertensive rat, two commonly used models of hypertension in which central and peripheral noradrenergic mechanisms are altered. The first study will test the hypothesis that activation of central D2 receptors results in an increase in blood pressure and sympathetic outflow in normotensive animals. This will be accomplished by injecting DA agonists and antagonists into the cerebroventricular system. The second study will identify the specific neurons that mediate the pressor effects of DA, and examine whether these responses are altered in hypertensive animals. This will be accomplished by microinjecting DA agonists and antagonists into specific cardiovascular regulatory regions of the hypothalamus and brainstem. The third study will test the hypothesis that the responsiveness of central monoaminergic neurons to DA is enhanced in hypertensive animals. Specifically, these experiments will examine whether D2 agonist administration differentially effects DA and noradrenaline stores in brain regions of hypertensive compared to normotensive rats. The fourth study will characterize alterations in the release of DA from central DA neurons in SHR and DOCA/NaCl treated rats. These experiments will employ direct in vitro and in vivo analysis of DA release from brain regions important in cardiovascular regulation. The results will provide the first direct demonstration of altered central DA function in an animal model of hypertension. Taken together, these studies will demonstrate the importance of the central DA system in cardiovascular control in normal and hypertensive individuals.
