MECHANISMS OF REFEEDING HYPERTENSION IN DIETARY OBESITY

虽然高血压与肥胖增加有关

Although hypertension is associated with increased adiposity in humans, evidence for a similar association in animals is thus far lacking. We recently initiated studies aimed at developing an animal model of human obese hypertension based on intermittant fasting and refeeding. These preliminary studies form the basis of this proposal. The goals of this proposal are threefold: 1. To continue preliminary work aimed at developing an animal model which may be useful in studying mechanisms of human obese hypertension further characterize the onset and progression of the hypertension and its relationship to body weight and food intake using animals chronically instrumented for measurement of systemic hemodynamics. This rat model is based on the observation that fat humans characteristically exhibit erratic swings in food intake, resulting in large and rapid weight loss and regain. Preliminary data presented in this proposal shows the development of a sustained, mild hypertension in obese rats similar to that seen in obese humans. 2. To investigate potential mechanisms responsible for the hypertension in this rodent model of obese hypertension. We will assess the putative role of the sympathetic nervous system (SNS), various vasoactive humoral agents and insulin in hypertension development by directly assaying these substances and through pharmacological interventions using known antagonist and agonist substances. In addition, we will directly measure several cardiovascular hemodynamic parameters and directly records sympathetic neural outflow in animals before, during and following hypertension development. We will analyze using quantitative receptor binding methodology changes in various organ adrenergic receptors. 3. The final aim of this proposal is to begin to examine the possible role of altered function of the paraventricular nucleus (PVN). The aims of this portion of the study are to begin to examine the possible alteration in function of a specific hypothalamic nucleus known to be involved in CNS autonomic control of the SNS and feeding. In summary, the proposed study will attempt to develop and refine a potential new rodent model useful in studying human obese hypertension and to thoroughly assess the possible role of the SNS and insulin in hypertension development. Also, the possible role of a specific hypothalamic structure in this pathophysiological state will be examined. The results of such a study may provide important new information related to human obese hypertension as well as provide a means for future animal studies of this problem.