Clinical trial NCT02102243: Neural Mechanism of Aldosterone-induced Insulin Resistance
Official title: The Role of Aldosterone on Sympathetic Nerve Activity and Insulin Sensitivity
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Hypertension
Keywords: hypertension
blood pressure
sympathetic nerve activity
vascular oxidative stress
nitric oxide
nitric oxide synthase (eNOS)
endothelium
endothelial dysfunction
endothelial cell protein expression
microvascular blood flow
flow mediated dilation
endothelial cell collection
microbubbles
Definity
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2014-04-02
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

Brief summary: Patients with high aldosterone hormone have higher blood glucose than normal people. This study is being done to understand how aldosterone hormone affects the nerve activity that controls blood flow in the muscles and blood glucose. The information may be helpful in selecting blood pressure medications which can improve not only blood pressure but also improve blood sugar.

Detailed description: Patients with primary aldosteronism are known to have impaired insulin sensitivity, which is improved after removal of aldosterone-producing adenoma. In patients with essential hypertension, plasma aldosterone levels have been also shown to positively correlate with indices of insulin resistance.

Mechanism underlying aldosterone-induced insulin resistance is unknown. Aldosterone has been shown to interfere with insulin signaling the vascular cells by increasing production of reactive oxygen species via activation of NADPH oxidase, resulting in decreased availability of nitric oxide (NO), the key mediator for insulin-mediated vasodilation. Treatment with mineralocorticoid receptor antagonists has been shown to improve insulin sensitivity in mice with obesity and metabolic syndrome. Aldosterone has also been shown to increase resting sympathetic vasoconstrictor activity to the peripheral circulation. However, effects of aldosterone and mineralocorticoid receptor antagonists on insulin-mediated skeletal muscle vasodilation, sympathetic activation, and vascular oxidative stress have not been assessed in humans.

The investigators will collect venous endothelial cells, and measure skeletal muscle microvascular perfusion using Octafluoropropane microbubble contrast agents, and measure sympathetic nerve activity in normotensive controls (NT), stage 1 essential hypertensive subjects (ET), and patients with primary aldosteronism (PA) during hyperinsulinemic euglycemic clamp.

Eligibility criteria: Inclusion Criteria:

1. Normotensive controls
2. Stage I (140-159/90-99 mmHg) untreated subjects with essential hypertension
3. Patients with PA and stage I (140-159/90-99 mmHg) hypertension

Exclusion Criteria:

1. Congestive heart failure or coronary artery disease
2. Blood pressure averaging \> 159/99 mmHg
3. Serum creatinine \> 1.5 mg/dL
4. Diabetes mellitus or other systemic illness
5. Left ventricular hypertrophy by echocardiography or ECG
6. Pregnancy
7. Hypersensitivity to spironolactone, chlorthalidone, amlodipine, human recombinant insulin or Definity
8. Any history of substance abuse (other than tobacco)
9. History of gouty arthritis
10. Patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts
11. Hypersensitivity to perflutren, blood, blood products or albumin

Primary outcomes:
measure: Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp
timeFrame: 1 day
Secondary outcomes:
measure: Change in microvascular blood flow during hyperinsulinemic euglycemic clamp.
timeFrame: 1 day
measure: Change in microvascular blood flow during saline infusion.
timeFrame: 1 day
measure: Change in endothelial cell protein expression after hyperinsulinemic euglycemic clamp
timeFrame: 1 day
measure: Change in endothelial cell protein expression after saline infusion
timeFrame: 1 day
measure: Increase in muscle sympathetic nerve activity during saline infusion
timeFrame: 1 day
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Wanpen Vongpatanasin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi G, Novello M, Favret G, Melis A, Cavarape A, Sechi LA. Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab. 2006 Sep;91(9):3457-63. doi: 10.1210/jc.2006-0736. Epub 2006 Jul 5.
citation: Donato AJ, Gano LB, Eskurza I, Silver AE, Gates PE, Jablonski K, Seals DR. Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H425-32. doi: 10.1152/ajpheart.00689.2008. Epub 2009 May 22.
citation: Colussi G, Catena C, Lapenna R, Nadalini E, Chiuch A, Sechi LA. Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients. Diabetes Care. 2007 Sep;30(9):2349-54. doi: 10.2337/dc07-0525. Epub 2007 Jun 15.
citation: Kontak AC, Wang Z, Arbique D, Adams-Huet B, Auchus RJ, Nesbitt SD, Victor RG, Vongpatanasin W. Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism. J Clin Endocrinol Metab. 2010 Oct;95(10):4756-61. doi: 10.1210/jc.2010-0823. Epub 2010 Jul 21.