The expression of the renin-angiotensin-aldosterone system in the skin and its effects on skin physiology and pathophysiology.

The local renin-angiotensin-aldosterone system (RAAS) is fully expressed in the human skin at the mRNA and protein level. Local RAAS is known to play a regulatory function in epidermal proliferation, wound healing, scarring, cutaneous heating adaptation, and aging. There are also some indications of its role in the regulation of hair growth and sebum secretion. Impaired wound healing, skin diseases associated with diabetes, cancer development, psoriasis, and scleroderma may be related to changes in skin RAAS activity. Extensive research has shown that RAAS-modulating drugs can affect the skin when applied orally or topically, creating new therapeutic approaches against dermatological diseases.

Nitric oxide as a modulator in platelet- and endothelium-dependent antithrombotic effect of eplerenone in diabetic rats.

We have recently demonstrated the antithrombotic effect of eplerenone on the arterial thrombotic process in diabetic rats associated with suppression of coagulation and enhancement of fibrinolysis. The aim of this study was to evaluate the role of platelets and endothelium in the mechanism of eplerenone antithrombotic action. Diabetes was induced in male Wistar rats with a single injection of streptozotocin (65 mg/kg). On the 25th day, treatment with eplerenone (100 mg/kg) was initiated for 10 days. Eplerenone did not change hemodynamic parameters (blood pressure, carotid blood flow, and heart rate), however, improved endothelium-dependent vasorelaxation in aortas and small mesenteric arteries, enhanced the aortic amounts of mRNA of endothelial nitric oxide synthase (eNOS), and reduced mRNA of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 2. A prolongation of bleeding time and decrease in platelet adhesion to collagen ex vivo was also observed. These changes were accompanied by prolonged time to occlusion and increased blood flow, and finally reduced thrombus mass in diabetic rats. The inhibition of NOS with L-NAME reduced the eplerenone antithrombotic effect. Our study provides evidence that the antithrombotic effect of eplerenone in diabetic rats is nitric oxide-dependent and associated with inhibiting the adhesion of platelets, as well as normalizing endothelial function. The mechanism of eplerenone antithrombotic action in diabetes is a result of improved endothelial nitric oxide bioavailability that leads to the improvement vascular and platelet function.

Beneficial effect of combined spironolactone and quinapril treatment on thrombosis and hemostasis in 2K1C hypertensive rats.

A strong correlation between raised aldosterone levels and increased risk of thrombotic disorders has been provided. Clinical studies have demonstrated the benefits of the addition of the aldosterone receptor antagonist to the standard therapy with angiotensin-converting enzyme inhibitor in the reduction of cardiovascular events in patients. We suggest that the benefits of this dual renin-angiotensin-aldosterone system (RAAS) blockade may be related to the drug's effects on the hemostatic and oxidative balance. Thus, we investigated the effect of combined spironolactone (SPIRO) and quinapril (QUIN) administration on thrombosis, hemostasis and oxidative stress in hypertensive rats. A two-kidney, one-clip model of renovascular hypertension in Wistar rats was used. QUIN, SPIRO, or QUIN + SPIRO were administered for 10 days. Venous thrombosis was induced by vena cava ligation. Thrombus weight and incidences of thrombosis were assessed. Bleeding time, platelet adhesion, tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), thrombin activatable fibrynolysis inhibitor (TAFI), malonyl dialdehyde, and hydrogen peroxide plasma levels were assayed. Aortic expression of NADPH oxidase and superoxidase dismutase were measured. We observed significant RAAS activation associated with hypercoagulability and oxidative stress augmentation in renovascular hypertensive rats. Thrombosis was reduced only in rats treated with QUIN + SPIRO. In all groups, decreases in TF, PAI-1, and TAFI levels were observed, however in the QUIN + SPIRO group those changes were more pronounced. The inhibition of platelet adhesion was also stronger in rats treated with QUIN + SPIRO. The oxidative stress parameters were markedly reduced in rats treated with QUIN or SPIRO, although the most evident changes were observed in the QUIN + SPIRO group. Dual RAAS blockade with aldosterone receptor antagonist and angiotensin-converting enzyme inhibitor provides additional benefits for experimental thrombosis associated with the antiplatelet, anticoagulative, profibrinolytic, and antioxidative effects in renovascular hypertensive rats.