The vascular endothelium produces a variety of factors that regulate the underlying vascular smooth muscle tone. Endothelium=dependent relaxation and contraction factors (EDRF and EDCF, respectively) have been extensively studied, but it was only in the last year and a half that an EDCF has been isolated and the synthetic peptide become available. Endothelin (ET- 1) was first isolated from porcine endothelial cells in culture and shown to be a 21 amino acid peptide with 4 cysteines and 2 disulphide bonds. It is the most powerful vasoconstrictor so far described. We have shown the existence of specific, high affinity receptors for ET- 1 in adrenal zona glomerulosa cells and have shown that it is a secretagogue for aldosterone and potentiates the action of Angiotensin II on the adrenal gland. We have also shown the presence of different subtypes of receptors for ET-1. We are hypothesizing that endothelin overproduction is involved in the pathogenesis of hypertension in some genetic animal models of hypertension and involved secondarily in induced models of rat hypertension. We are also postulating a pathogenic role for endothelin during the malignant phase of hypertension, whatever the initiating cause. We have developed a RIA for ET- 1. We will use this assay to measure ET- 1 in the perfusiate from inferior mesenteric artery isolated from rats during the development of hypertension. We will study the SHR and WKY controls, Dahl S/JR and R/JR and Sprague-Dawley controls, and DOCA-salt hypertension. We will also measure receptor number and affinity in vascular smooth muscle cells in culture obtained from aortas of SHR, NM control, Dahl S/JR, R/JR, and Sprague-Dawley rats. A second hypothesis is that endothelin plays a role in modulating the differentiation and responsiveness of adrenal cells to other agents. We have shown that endothelin stimulates aldosterone secretion. We will study the mitogenic and cell proliferative actions of endothelin and its ability to modify steroidogenic pathways in glomerulosa primary cultures, as well as characterize the ET- 1 receptor subtypes of the adrenal zona glomerulosa. We will also determine if ET- 1 plays a physiological role in the whole animal and will infuse intraarterially proximally to the adrenal artery and will determine aldosterone secretory rates from the left adrenal.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Renal Study Section (CVB)
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University of South Florida
Schools of Medicine
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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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