Studies on the mechanism of mineralocorticoid-induced hypertension: evidence for the presence of an In-Situ mechanism in the arterial wall for a direct action of mineralocorticoids

Abstract

Data from clinical and experimental studies indicate that mechanism(s) for action of mineralocorticoids. other than renal. must be involved in the overall effect of mineralocorticoids on circulation — increased peripheral resistance and hypertension. We have postulated existence of such a mechanism in the arterial wall and have looked for the evidence of its presence. We have found high affinity, specific binders for mineralocorticoids, and glucocorticoids. with characteristics of steroid receptors, in rabbit and lamb arterial homogenate cytosol. Moreover, these binders were found to possess also other fundamental properties of cytoplasmic steroid receptors: they translocate to cell nuclei (as steroid-receptor complexes) and bind to relatively specific “acceptor-sites” on nuclear chromatin. The mineralocorticoid with the highest affinity for the arterial mineralocorticoid receptor is 11-desoxycorticosterone (DOC); however, the possibility of a parallel existence of a specific aldosterone receptor is not ruled out. Cytoplasmic mineralocorticoid receptors are not present in veins. The steroid with the highest affinity for the arterial glucocorticoid receptor is dexamethasone. similarly as in other target tissues to glucocorticoids. A highly specific transcortinlike cortisol binder was also found in aorta cytosol. In parallel with this binder a true cortisol-receptor (translocating to cell nuclei and binding to nuclear chromatin) was also found. This points to heterogeneity of cytoplasmic glucocorticoid receptors. Furthermore, we have studied the effect of chronic administration of DOC acetate (DOCA) on intracellular sodium concentration [Na i .] and on the rate of passive Na + -influx into the cells of aorta. Both were found to be significantly higher in DOCA-induced hypertensive rabbits than in normotensive control animals. This indicates that cell-membrane permeability to electrolytes is increased as a result of chronic elevation of circulating levels of DOC, and is in accord with the findings of other investigators in other animal species. We postulate that this effect of DOC is elicited through the receptor-mediated mechanism for action of mineralocorticoids in the arterial wall; and that increased [Na i ] in arterial and arteriolar smooth muscles leads to their increased contractility, hyperresponsiveness to vasoconstrictive stimuli, hypertrophy, increased peripheral resistance, and hypertension.