Aldosterone and Vascular Disease in Diabetes Mellitus

• Coronary microvascular function assessed by myocardial perfusion reserve measured by MRI [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  

• Endothelial dysfunction assessed by brachial artery reactivity [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  
• Inflammation and cellular oxidative stress and injury, assessed by CRP, MCP-1, PAI-1, nephrin, cystanin C, F2 isoprostanes, and urinary 12-HETE [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  
• Proteinuria [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  

Recent human and animal studies suggest that activation of the mineralocorticoid receptor (MR) by aldosterone, the final product of the renin-angiotensin-aldosterone system, causes microvascular damage, vascular inflammation, and endothelial dysfunction. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are unable to provide long-term aldosterone suppression. Therefore, we hypothesize that activation of the MR contributes to progression of vascular disease in patients with diabetes already using ACE inhibitor therapy.

Specific aims for this proposal are to determine in patients with type 1 or type 2 diabetes mellitus and proteinuria, already receiving ACE inhibitor or ARB therapy, the effects of an aldosterone receptor antagonist vs. hydrochlorothiazide on:

1. Coronary microvascular function assessed by MRI perfusion reserve,
2. Endothelial dysfunction assessed by brachial artery reactivity studies,
3. Inflammation and cellular oxidative stress and injury, assessed by c-reactive protein (CRP), MCP-1, plasminogen activator inhibitor-1 (PAI-1).
4. Proteinuria and whether there is a differential effect when a MR antagonist or HCTZ is added to the ACE inhibitor therapy.

This is a double-blind, randomized, cross-over study of men and women (21-64 years old) with type 1 or type 2 diabetes mellitus and albuminuria (³30 mg/g creatinine). Participants will be randomized to a MR antagonist + placebo or HCTZ + potassium supplementation for 6 weeks. The MR antagonist arm will receive eplerenone 50 mg daily. The HCTZ arm will receive HCTZ 12.5 mg with potassium 10 Meq daily. Amlodipine 5 to 10 mg daily will be added during run phase to control blood pressure. Blood pressure goal is less than 130/80 mm Hg. There will be a 4-week washout period before the patients are crossed-over to the other study arm. MRI perfusion reserve, brachial artery reactivity, and blood samples will be obtained at the beginning and end of each treatment arm.