Aldosterone is a powerful mineralocorticoid, which plays a significant role in the pathogenesis of several forms of human and experimental hypertension. In excess it is also responsible for direct deleterious effects on the heart, and cerebral and renal vasculature, independent of its effect on the blood pressure. The applicant has demonstrated that Aldosterone biosynthesis occurs in vascular tissues and the brain, in addition to the adrenal zona glomerulosa. The amount of aldosterone synthesis in the brain is very small, but it may have paracrine effects through receptors located within a short distance of its site of synthesis. They have published evidence supporting the action of central mineralocorticoids in the hypertension of the Dahl Salt-Sensitive rat. The concentration of aldosterone in the brain is higher than that in plasma, even in normal outbred rats. A significant proportion, approximately 2/3, occurs as low polarity acyl esters of aldosterone. Acyl esters of several steroids are reported to accumulate in the CNS. They found the presence of two different aldosterone acyl esters, an oleate, and what may be one of the three possible aldosterone monoactates isomers. Preliminary evidence suggests that acylation of aldosterone increases its biological activity in vivo. They propose the hypothesis that: Aldosterone action in brain is potentiated or prolonged by acylation.
The specific aims to test this hypothesis are 1) Isolation and elucidation of the structures of acyl esters of aldosterone found in the brain. 2) Measurement of aldosterone acyl esters in the serum and specific areas of the brain in normal and pathophysiologic conditions. 3) Assessment of the hypertensinogenic activities of the aldosterone acyl esters. 4) Study of the metabolism of aldosterone and corticosterone and the regulation of the synthesis of low polarity derivatives in the brain, including the identification of the sites of formation of aldosterone acyl esters.
| Gomez-Sanchez, Elise P (2016) Third-generation Mineralocorticoid Receptor Antagonists: Why Do We Need a Fourth? J Cardiovasc Pharmacol 67:26-38 |
| Gomez-Sanchez, Elise P (2015) Salt-sensitive hypertension: food for thought. Hypertension 65:283-4 |
| Gomez-Sanchez, Elise; Gomez-Sanchez, Celso E (2014) The multifaceted mineralocorticoid receptor. Compr Physiol 4:965-94 |
| Gomez-Sanchez, Elise P (2014) Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis. Steroids 91:20-31 |
| Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E (2012) Central regulation of blood pressure by the mineralocorticoid receptor. Mol Cell Endocrinol 350:289-98 |
| Gomez-Sanchez, Elise P (2011) Mineralocorticoid receptors in the brain and cardiovascular regulation: minority rule? Trends Endocrinol Metab 22:179-87 |
| Gomez Sanchez, Elise P (2009) Central mineralocorticoid receptors and cardiovascular disease. Neuroendocrinology 90:245-50 |
| Gomez-Sanchez, Elise P; Samuel, Jacqueline; Vergara, Gaston et al. (2005) Effect of 3beta-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat. Am J Physiol Regul Integr Comp Physiol 288:R389-93 |
| Gomez-Sanchez, Elise P; Ahmad, Naveed; Romero, Damian G et al. (2005) Is aldosterone synthesized within the rat brain? Am J Physiol Endocrinol Metab 288:E342-6 |
| Gomez-Sanchez, Elise P; Ahmad, Naveed; Romero, Damian G et al. (2004) Origin of aldosterone in the rat heart. Endocrinology 145:4796-802 |
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