eplerenone and Diabetes-Mellitus--Type-1

Impaired coronary circulatory function predicts cardiovascular events, the leading cause of death in patients with diabetes mellitus. Aldosterone causes cardiovascular injury and is not suppressed by chronic angiotensin converting enzyme (ACE) inhibitor therapy.. Our objective was to assess whether mineralocorticoid receptor activation contributes to coronary circulatory dysfunction in patients with diabetes who are already receiving ACE inhibitor therapy.. A randomized, double-blind, crossover study with an intervening washout period of at least 4 wk was conducted with ambulatory patients from the community.. Patients included 16 subjects (11 men, eight Caucasians; mean age, 53 yr; mean body mass index, 38.0 kg/m2) with diabetes and albuminuria but without clinical cardiovascular disease.. ACE inhibitors were switched to enalapril 20 mg daily, and other antihypertensives were discontinued. Amlodipine 5-10 mg daily was added to achieve blood pressures less than 130/80 mm Hg. Subjects then received, in random order, 6 wk of the mineralocorticoid receptor antagonist eplerenone 50 mg (with placebo pill) daily and 6 wk of another diuretic, hydrochlorothiazide 12.5 mg (with potassium 10 mEq) daily.. Before and after each 6-wk treatment period, we measured coronary circulatory function (adenosine-stimulated myocardial perfusion reserve) and endothelial function (brachial artery reactivity and peripheral arterial tonometry).. The eplerenone and hydrochlorothiazide groups had similar blood pressures, serum potassium, glycemia, and endothelial function. Although pretreatment myocardial perfusion reserve did not differ between groups, myocardial perfusion reserve was significantly higher after eplerenone than after hydrochlorothiazide (median 1.57 vs. 1.30; P = 0.03).. Mineralocorticoid receptor blockade improves coronary circulatory function compared with hydrochlorothiazide in patients with diabetes already receiving ACE inhibitor therapy.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Brachial Artery; Coronary Circulation; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Eplerenone; Female; Humans; Hydrochlorothiazide; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Pilot Projects; Potassium; Renal Circulation; Spironolactone

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFbeta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.

Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Hypertrophy; Kidney; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Osteopontin; Rats; Rats, Wistar; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone; Streptozocin; Systole