GENETIC HYPERTENSION AND SYMPATHETIC MECHANISMS

本提案的目的是：1)识别并开始

The aims of this proposal are: 1) to identify and start development of genetically hypertensive strains of rabbits with a common congenic control; 2) to determine the number of genes controlling hypertension in each strain; 3) to make physiological and biochemical measurements of sympathetic nervous system activity within the strains; 4) to use DNA probes specific for genes expressed in the sympathetic nervous system to identify genetic differences between strains and 5) to make these strains available to other investigators. The hypertensive strains will have a truly congenic normotensive control and will share the same genetic background themselves. Hypertensive rabbits from disparate rabbitries will be mated with rabbits from a normotensive, inbred strain (Strain III, Jackson Labs). The genes from hypertensive animals will not be mixed (as done by other investigators) in order to simplify identification of individual genetic and physiological factors causing hypertension. Blood pressure will be measured by an indirect ear artery method in F1 rabbits between 2 and 5 months of age to determine onset of hypertension. Pressure will be measured by a direct method for selection of rabbits with highest pressures to mate with controls for first backcross, N1. F1 and N1 to N4 generations of rabbits will be used also for genetic studies to determine the numbers of genes causing hypertension and to identify, by DNA probes, components of the sympathetic nervous system regulated genetically. Also studies of indices of sympathetic activity will include, in the conscious rabbit, response to a cold pressor test and reflex bradycardia during activation of arterial baroreceptors. Additionally, activities of two catecholamine synthetic enzymes will be assayed in various tissues and neuronal accumulation of norepinephrine (NE) and contractility response to NE will be assessed in blood vessels. Light and electron microscopy will be used for morphometric studies of vessels. All these studies will be evaluated with respect to levels of arterial pressure. Such data are not available in the literature at present. In summary, we shall create a tool for study of hypertension that will be of maximum usefulness to other researchers. Its outstanding virtues are: isolation in a uniform state of a sample of several different hypertensive genotypes and appropriate controls will be available for all studies since hypertensive strains are congenic with each other and with inbred normotensive strain.