The antithrombotic effect of angiotensin-(1—7) closely resembles that of losartan

Abstract

Angiotensin-(1-7) [Ang-(1-7)] is the bioactive peptide which may be responsible for some of the pharmacological effects of losartan. Our previous study has demonstrated the antithrombotic action of losartan in a model of experimental thrombosis. In the present study, we compared the antithrombotic action of losartan and Ang-(1-7). Acute (10 mg/kg, p.o.) and chronic (10 mg/kg, p.o., three weeks) losartan administration to spontaneously hypertensive rats (SHR) induced a decrease in thrombus weight (1.6 +/- 0.6 mg and 1.2 +/- 0.3 mg respectively vs. control 2.9 +/- 0.8 mg; p<0.05, p<0.05). A similar reduction was observed in two-kidney, one-clip hypertensive rats (2K-IC)receiving acute losartan administration (1.39 +/- 0.29 mg vs. 3.25 +/- 0.62 mg; p<0.01). Infusion of Ang-(1-7) to2K-lC rats also reduced the thrombus weight(1.01 +/- 0.34 mg, 1.23 +/- 0.38 mg and 2.17 +/- 0.36 mg for 1, 10, 100 pmol/kg/min, respectively vs. 3.58 +/- 0.6 mg control; p<0.01, p<0.01, p<0.05). Losartan produced a decrease in systolic blood pressure (BP) in SHR as well as in 2K-1C rats, while Ang-(1-7) infusion had no effect on BP. Acute losartan dosing to 2K-1C rats decreased platelet adhesion to fibrillar collagen(24.9 +/- 1.0% vs. control 31.5 +/- 1.1%, p<0.001). The incubation of platelet samples with Ang-(1-7) (10-6 and 10 5 M) also reduced adhesion to fibrillar collagen(38.4 +/- 0.1% and 33.8 +/- 0.8% respectively vs. control 40.0 +/- 0.6%; p<0.05, p<0.001). There were no apparent changes in prothrombin time, activated partial thromboplastin time and euglobulin clot lysis time in losartan and Ang-(1-7)-treated groups. We conclude that, like losartan, Ang-(1-7) is able to act as an antithrombotic agent.

ACE2 Activation Promotes Antithrombotic Activity

“…Moreover, it is well established from previous studies that platelets express the AT 1 receptor and its activation by Ang II potentiates platelet activation and aggregation (21)(22)(23). On the other hand, Ang-(1-7) has been described as an antithrombotic peptide (24). Kucharewicz et al (24,25) have shown that intravenous infusion of Ang-(1-7) produces a potent reduction in thrombus formation in renovascular hypertensive rats.…”

“…Kucharewicz et al (24,25) have shown that intravenous infusion of Ang-(1-7) produces a potent reduction in thrombus formation in renovascular hypertensive rats. Furthermore, these authors also found that the intrinsic antithrombotic effects of the antihypertensive drugs captopril (ACE inhibitor) and losartan (AT 1 receptor blocker) were attenuated by the selective Ang-(1-7) receptor antagonist A-779 (24,25). More recently, it was demonstrated that the Ang-(1-7) receptor Mas is present in platelets and the interaction between Ang-(1-7) and Mas on platelets promotes nitric oxide (NO) production, which is a major antiplatelet agent (26).…”

Angiotensin-(1-7) Inhibits Growth of Human Lung Adenocarcinoma Xenografts in Nude Mice through a Reduction in Cyclooxygenase-2

“…Increased incidence of thrombotic events (myocardial infarction, angina, and stroke) was reported in clinical trials using the selective COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex) for the treatment of colon cancer. However, studies show that Ang-(1-7) caused a decrease in thrombus weight following vena cava occlusion as well as reduced collagen adhesion to platelets in two-kidney, one-clip hypertensive rats (37). An increase in plasminogen-activated inhibitor-1 and tissue plasminogen activator was also observed in cultured human umbilical endothelial vessels treated with Ang- (1-7) (ref.…”

Endothelial Cell Regulation of Pulmonary Vascular Tone, Inflammation, and Coagulation

“…The interplay between Ang-(1-7) and NO extends into platelets and clotting pathways as well. Ang-(1-7) enhances NO production, and inhibits platelet aggregation (117,182,183). This antiaggregative effect is mediated by Ang-(1-7)-induced stimulation of NO release from platelets (71).…”