Hyperglycemia Potentiates Prothrombotic Effect of Aldosterone in a Rat Arterial Thrombosis Model.

We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 µg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10-7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions.

New agents modulating the renin-angiotensin-aldosterone system-Will there be a new therapeutic option?

The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of the RAAS: (1) angiotensin-converting enzyme (ACE)-angiotensin II-AT1 receptor axis and (2) ACE2-angiotensin-(1-7)-Mas receptor axis. The activation of the first axis leads to deleterious effects, including vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis; therefore, blocking the components of this axis is a highly rational and commonly used therapeutic procedure. The ACE2-Ang-(1-7)-Mas receptor axis has a different role, since it often opposes the effects induced by the classical ACE-Ang II-AT1 axis. Once the positive effects of the ACE2-Ang-(1-7)-Mas axis were discovered, the alternative ways of pharmacotherapy activating this axis of RAAS appeared. This article briefly describes new molecules affecting the RAAS, namely: recombinant human ACE2, ACE2 activators, angiotensin-(1-7) peptide and non-peptide analogs, aldosterone synthase inhibitors, and the third and fourth generation of mineralocorticoid receptor antagonists. The results of the experimental and clinical studies are encouraging, which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders.

Eplerenone reduces arterial thrombosis in diabetic rats.

INTRODUCTION: 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. MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic rats were treated with EPL (100 mg/kg/day) for 10 days. Thrombosis in the carotid artery was stimulated electrically. RESULTS: 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-1ß plasma levels. CONCLUSIONS: 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.

[Prothrombotic aldosterone action--a new side of the hormone]. / Prozakrzepowe dzialanie aldosteronu--nowe oblicze hormonu.

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.