Mineralocorticoid Receptor (MR) Antagonist (Eplerenone) vs Amlodipine and STRIATIN
Summary
Salt sensitivity of blood pressure is a substantial risk factor for cardiovascular morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension and salt sensitive blood pressure. Key homeostatic mechanisms that regulate renal sodium reabsorption are: first, hormonal, e.g., renin-angiotensin-aldosterone system and second, vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to hypertension and salt sensitive blood pressure. The investigators recently documented that striatin plays a novel role in the development of salt sensitive blood pressure. However, the mechanisms that lead to striatin-mediated salt sensitive blood pressure are not clear; defining these mechanisms is the overall goal of this proposal. Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to the mechanism of action of steroids. In a large study of well characterized subjects from the International Hypertensive Pathotype (HyperPATH) cohort, the investigators documented that hypertensive and normotensive humans who are striatin risk allele carriers have salt sensitive blood pressure. The investigators then developed a striatin heterozygous knockout mouse as a tool to identify potential mechanisms for the salt sensitive blood pressure. The investigators documented that these mice also have salt sensitive blood pressure with higher blood pressure levels and inappropriately increased aldosterone levels on a liberal salt diet.
Timeline
- Start
- 2019-01-15
- Primary completion
- 2023-08-28
- Completion
- 2024-01-31
Publications
- Results Coutinho P, Vega C, Pojoga LH, Rivera A, Prado GN, Yao TM, Adler G, Torres-Grajales M, Maldonado ER, Ramos-Rivera A, Williams JS, Williams G, Romero JR. Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action. Endocrinology. 2014 Jun;155(6):2233-43. doi: 10.1210/en.2013-1834. Epub 2014 Mar 21.
- Results Garza AE, Rariy CM, Sun B, Williams J, Lasky-Su J, Baudrand R, Yao T, Moize B, Hafiz WM, Romero JR, Adler GK, Ferri C, Hopkins PN, Pojoga LH, Williams GH. Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans. Hypertension. 2015 Jan;65(1):211-217. doi: 10.1161/HYPERTENSIONAHA.114.04233. Epub 2014 Nov 3.
- Results Pojoga LH, Coutinho P, Rivera A, Yao TM, Maldonado ER, Youte R, Adler GK, Williams J, Turchin A, Williams GH, Romero JR. Activation of the mineralocorticoid receptor increases striatin levels. Am J Hypertens. 2012 Feb;25(2):243-9. doi: 10.1038/ajh.2011.197. Epub 2011 Nov 17.
- Results Garza AE, Pojoga LH, Moize B, Hafiz WM, Opsasnick LA, Siddiqui WT, Horenstein M, Adler GK, Williams GH, Khalil RA. Critical Role of Striatin in Blood Pressure and Vascular Responses to Dietary Sodium Intake. Hypertension. 2015 Sep;66(3):674-80. doi: 10.1161/HYPERTENSIONAHA.115.05600. Epub 2015 Jul 13.
- Results Baudrand R, Pojoga LH, Romero JR, Williams GH. Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):32-7. doi: 10.1097/01.mnh.0000436543.48391.e0.
- Results Vaidya A, Underwood PC, Hopkins PN, Jeunemaitre X, Ferri C, Williams GH, Adler GK. Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension. 2013 Apr;61(4):886-93. doi: 10.1161/HYPERTENSIONAHA.111.00662. Epub 2013 Feb 11.
- Results Brown JM, Williams JS, Luther JM, Garg R, Garza AE, Pojoga LH, Ruan DT, Williams GH, Adler GK, Vaidya A. Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone. Hypertension. 2014 Feb;63(2):273-80. doi: 10.1161/HYPERTENSIONAHA.113.01910. Epub 2013 Nov 4.
- Results Baudrand R, Pojoga LH, Vaidya A, Garza AE, Vohringer PA, Jeunemaitre X, Hopkins PN, Yao TM, Williams J, Adler GK, Williams GH. Statin Use and Adrenal Aldosterone Production in Hypertensive and Diabetic Subjects. Circulation. 2015 Nov 10;132(19):1825-33. doi: 10.1161/CIRCULATIONAHA.115.016759. Epub 2015 Oct 2.
- Results Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH, Garg R. Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab. 2007 Nov;92(11):4472-5. doi: 10.1210/jc.2007-1088. Epub 2007 Aug 28.
- Results Garg R, Williams GH, Hurwitz S, Brown NJ, Hopkins PN, Adler GK. Low-salt diet increases insulin resistance in healthy subjects. Metabolism. 2011 Jul;60(7):965-8. doi: 10.1016/j.metabol.2010.09.005. Epub 2010 Oct 30.
- Results Pojoga LH, Underwood PC, Goodarzi MO, Williams JS, Adler GK, Jeunemaitre X, Hopkins PN, Raby BA, Lasky-Su J, Sun B, Cui J, Guo X, Taylor KD, Chen YD, Xiang A, Raffel LJ, Buchanan TA, Rotter JI, Williams GH. Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension. J Clin Endocrinol Metab. 2011 Aug;96(8):E1288-92. doi: 10.1210/jc.2010-2738. Epub 2011 May 25.
- Results Underwood PC, Sun B, Williams JS, Pojoga LH, Chamarthi B, Lasky-Su J, Raby BA, Hopkins PN, Jeunemaitre X, Brown NJ, Adler GK, Williams GH. The relationship between peroxisome proliferator-activated receptor-gamma and renin: a human genetics study. J Clin Endocrinol Metab. 2010 Sep;95(9):E75-9. doi: 10.1210/jc.2010-0270. Epub 2010 Jul 14.
- Results Underwood PC, Sun B, Williams JS, Pojoga LH, Raby B, Lasky-Su J, Hunt S, Hopkins PN, Jeunemaitre X, Adler GK, Williams GH. The association of the angiotensinogen gene with insulin sensitivity in humans: a tagging single nucleotide polymorphism and haplotype approach. Metabolism. 2011 Aug;60(8):1150-7. doi: 10.1016/j.metabol.2010.12.009. Epub 2011 Feb 8.
- Results Pojoga LH, Romero JR, Yao TM, Loutraris P, Ricchiuti V, Coutinho P, Guo C, Lapointe N, Stone JR, Adler GK, Williams GH. Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II. Endocrinology. 2010 Mar;151(3):1236-46. doi: 10.1210/en.2009-0514. Epub 2010 Jan 22.
- Results Chong C, Hamid A, Yao T, Garza AE, Pojoga LH, Adler GK, Romero JR, Williams GH. Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling. J Endocrinol. 2017 Mar;232(3):525-534. doi: 10.1530/JOE-16-0452. Epub 2017 Jan 17.
- Results Pojoga LH, Yao TM, Sinha S, Ross RL, Lin JC, Raffetto JD, Adler GK, Williams GH, Khalil RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1258-65. doi: 10.1152/ajpheart.01014.2007. Epub 2008 Jan 4.
- Stone IB, Green JAEM, Koefoed AW, Hornik ES, Williams JS, Adler GK, Williams GH. Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design. Pharmacogenet Genomics. 2021 Jun 1;31(4):83-88. doi: 10.1097/FPC.0000000000000425.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Amlodipine | Other / unclassified | 2.5 mg | — |
| Subject | Amlodipine | Other / unclassified | 5 mg | — |
| Subject | Amlodipine | Other / unclassified | 10 mg | — |
| Subject | Eplerenone | Unknown | 50 mg | — |
| Subject | Eplerenone | Unknown | 100 mg | — |
| Subject | Eplerenone | Unknown | 200 mg | — |