eplerenone and Thrombosis

Recent studies have focused on a new wave of interest in aldosterone due mainly to its growing profile as a local messenger in pathology of the cardiovascular system, rather than its hormonal action. In the last few years strong evidence for a correlation between raised aldosterone level and haemostasis disturbances leading to increased risk of cardiovascular events has been provided. It has been demonstrated that aldosterone contributes to endothelial dysfunction, fibrinolytic disorders and oxidative stress augmentation. It was also shown that chronic aldosterone treatment results in enhanced experimental arterial thrombosis. Our study in a venous model of thrombosis in normotensive rats confirmed that even a short-lasting increase in aldosterone level intensified thrombus formation. One-hour aldosterone infusion shortened bleeding time; increased platelet adhesion to collagen; reduced tissue factor, thrombin activatable fibrinolysis inhibitor, and plasminogen activator inhibitor; and increased plasminogen activator plasma level. A fall in plasma nitric oxide metabolite concentration with a decrease in aortic nitric oxide synthase mRNA level was also observed. Moreover, aldosterone increased hydrogen peroxide and malonyl dialdehyde plasma concentration and augmented NADPH oxidase and superoxide dismutase aortic expression. Therefore, the mechanism of aldosterone prothrombotic action is multiple and involves primary haemostasis activation, procoagulative and antifibrinolytic action, NO bioavailability impairment and oxidative stress augmentation. The effects of aldosterone were not fully abolished by mineralocorticoid receptor blockade, suggesting the involvement of alternative mechanisms in the prothrombotic aldosterone action.

Topics: Aldosterone; Animals; Eplerenone; Hemostasis; Platelet Adhesiveness; Rats; Spironolactone; Thrombosis

Aldosterone is known to have multiple adverse cardiovascular effects that are reminiscent of but independent from angiotensin II. These effects include endothelial dysfunction, heightened thrombogenicity, inflammation, and reparative fibrosis, and have been described in experimental and human models of aldosterone excess. Recently a number of clinical investigations have demonstrated that mineralocorticoid receptor (MR) antagonism, even in conditions not traditionally associated with systemic activation of the renin-angiotensin II-aldosterone pathway, may provide additional benefits above and beyond angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockade. The Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS) with eplerenone in patients who were post-myocardial infarction underscores the additive benefit of such a strategy in post-infarction patients that typify an at-risk population for recurrent cardiovascular events. The mechanisms operative in acute coronary syndromes (ACS), including inflammation, altered hemostasis, and endothelial dysfunction, overlap significantly with those seen in the EPHESUS patient population. One may therefore hypothesize that MR antagonism with eplerenone may be beneficial in patients with ACS. Another advantage of using eplerenone is that it offers the advantages of MR antagonism without the side effects due to blockade of other nuclear receptors such as the androgen and progesterone receptors. If MR blockade is found to be beneficial in patients with ACS, the potential reduction in morbidity, mortality, and health care costs are profound.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Collagen; Coronary Restenosis; Eplerenone; Humans; Inflammation; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Syndrome; Thrombosis

Clinical studies demonstrated the benefits of eplerenone (EPL) in reduction of cardiovascular events in diabetic patients. Since acute myocardial infarction (AMI) and stroke are related to acute intravascular thrombosis, we postulate that the beneficial effects of EPL may result from its antithrombotic action.. Streptozotocin (STZ)-induced diabetic rats were treated with EPL (100 mg/kg/day) for 10 days. Thrombosis in the carotid artery was stimulated electrically.. Thrombosis development was enhanced in STZ-induced diabetic rats as compared to normoglycaemic controls. EPL caused prolongation of the time to artery occlusion, reduction in the incidence of occlusion and decrease in thrombus weight. Changes in the thrombi structure and the inhibition of hypertrophy of the tunica media in the artery wall were also observed. EPL caused reduction in tissue factor, plasminogen activator inhibitor type 1 and interleukin-1β plasma levels.. Our study demonstrated the antithrombotic effect of EPL manifested by a decrease in the dynamics of thrombus formation and changes in its structure. The changes in thrombosis process were accompanied by antihaemostatic, profibrinolytic and anti-inflammatory effects. The aldosterone blockade with EPL seems to be an additional pharmacological strategy for the prevention and treatment of thrombotic disorders in diabetes.

Topics: Animals; Carotid Arteries; Diabetes Mellitus, Experimental; Eplerenone; Hemostasis; Interleukins; Male; Rats, Wistar; Regional Blood Flow; Spironolactone; Thrombosis; Vascular Patency

Topics: Aldosterone; Animals; Blood Coagulation; Blood Pressure; Carboxypeptidase B2; Disease Models, Animal; Eplerenone; Infusions, Intravenous; Male; Mineralocorticoid Receptor Antagonists; Plasminogen Activator Inhibitor 1; Rats; Rats, Wistar; Receptors, Mineralocorticoid; Spironolactone; Thromboplastin; Thrombosis; Tissue Plasminogen Activator