Mineralocorticoid excess in combination with high salt intake is known to produce hypertension in several animal species, including humans. Despite extensive investigation into the mechanisms of mineralocorticoid-salt hypertension, the factors that contribute to its genesis and maintenance are as yet unclear. In this proposal, the physiological response to the mineralocorticoid aldosterone will be compared in two strains of rats: the Wistar rat, which develops hypertension when treated with aldosterone and salt, and the Wistar-Furth rat, which is resistant to this form of hypertension. These experiments represent a unique approach to the study of mineralocorticoid-salt hypertension because it will be possible to determine which responses to aldosterone may be important for the hypertension (occur only in Wistar rats) and which responses can be separated from the hypertension (occur in both rat strains). Increased contractile sensitivity of isolated vascular preparations to vasoconstrictors is characteristic of this model of hypertension. I hypothesize that a lack of increased vascular reactivity to vasoconstrictors is a mechanism that confers resistance to aldosterone-salt hypertension on the Wistar-Furth rat. Furthermore, I hypothesize that another mechanism that has been implicated in mineralocorticoid-salt hypertension, salt and water retention, will be intact in Wistar-Furth rats. To test these hypotheses, I propose experiments designed to address five specific aims: 1) do changes in vascular contractile sensitivity (isolated helically-cut carotid arteries) that occur in Wistar rats treated with aldosterone and high salt intake also occur in Wistar-Furth rats?, 2) are changes in vascular reactivity associated with a decreased ability of calcium to stabilize the vascular smooth muscle cell membrane?, 3) are the effects of aldosterone-salt treatment on water and electrolyte handling the same in the two strains?, 4) are there differences in aldosterone binding site number or affinity in the vasculature, kidney, or brain?, and 5) are Wistar-Furth rats resistant to other sodium-dependent or volume-dependent forms of experimental hypertension? Successful completion of these experiments should yield unique information regarding physiological mechanisms that are important in the pathogenesis of mineralocorticoid-salt hypertension.
| Magazine, H I; Andersen, T T; Bruner, C A et al. (1994) Vascular contractile potency of endothelin-1 is increased in the presence of monocytes or macrophages. Am J Physiol 266:H1620-5 |
