Are we content with lowering blood pressure alone, or should we be asking something more from the antihypertensive drugs we use?: effects of antihypertensive agents on fibrinolytic function

Abstract

The fibrinolytic system plays an important role preventing intravascular thrombosis. The process of fibrinolysis is influenced by the intimate interactions between plasminogen activators (such as tissue plasminogen activator (t-PA) that promotes fibrinolysis) and inhibitors that modulate this activity (such as plasminogen activator inhibitor-1 (PAI-1)) -however, the net effect of the fibrinolytic system is mediated by activation of plasminogen to plasmin. 1 Plasmin is a serine protease that cleaves fibrin into soluble fragments, but shows other important functions, including increasing the activity of matrix metalloproteinases, 2 which degrade collagen and glycoproteins in atherosclerotic plaques, and thus, may be responsible for vascular remodelling. Plasmin also activates transforming growth factorbeta, an anti-inflammatory cytokine that inhibits migration and proliferation of smooth muscle cells, being of crucial importance in the early stages of atherosclerosis. 3 Structural and functional changes in vascular endothelium, which could be interpreted as a response to injury to the cell, may be involved in the development of vascular disease.Increasing evidence also suggests that an imbalance between t-PA and PAI-1 is of huge importance for the cardiovascular system. Indeed, established atherosclerotic disease is associated with changes in the endothelial function, as is the presence of its well-defined risk factors (eg smoking, diabetes, hypertension and hyperlipidaemia). 4 As endothelial cells release t-PA and PAI-1, it has been suggested that these could also be markers of endothelial cell damage or dysfunction. 5,6 Indeed, patients with cardiovascular risk factors demonstrate differences in t-PA and PAI-1 levels, and reduced activity of fibrinolytic function (lower t-PA activity and higher levels of PAI-1) has been reported in patients with hypertension and hypercholesterolemia, 7,8 as well as in diabetes. 9 Hence, raised concentrations of t-PA antigen have been associated with acute coronary syndromes 10,11 and stroke. 12 One aspect, which has to be taken into account, is the distinction between the measurement of activity and antigen levels of t-PA and PAI-1, as they represent very different things. The total amount of t-PA antigen that has been secreted is approximately equal to active t-PA plus t-PA/PAI-1 complex, being only a few percent of t-PA antigen functionally active. Hence, elevated t-PA antigen levels do not necessarily reflect an activation of the fibrinolytic system. Indeed, high plasma t-PA antigen concentrations are probably a marker for high PAI-1 concentrations and low intrinsic fibrinolytic activity. 13 Moreover, a relationship among t-PA antigen levels and markers of inflammation and endothelial damage has also been described. 14 While the blood vessels are exposed to high pressures in patients with hypertension, the main complications related to hypertension, such as myocardial infarction or stroke, are paradoxically thrombotic rather than haemorrhagic, the so-called

Hypertension, aortic sclerosis and the prothrombotic state: understanding the complex interaction

“…There is a new concept of not being simply content with just lowering blood pressure and we must tailor the antihypertensive therapy depending on the individual patient and the cardiovascular risk profile. 17 The paper by Iida et al 3 also reports that treatment with valsartan reduced the levels of prothrombin F1 þ 2 in hypertensive patients consistent with previous data in which the treatment of hypertension led to an improvement in the thrombotic profile. 18 In patients with AVS, the levels of the markers of thrombin generation did not differ from baseline, even after 6 months of treatment.…”

Cardiovascular Risk Assessment in Diabetes and Chronic Kidney Diseases: A New Insight and Emerging Strategies

“…According to a recent study Losartan improves resistance artery lesions and prevents TGF-ß production in untreated hypertensive patients [245]. In addition, ACE-I agents potentiate bradykinin-induced tissue plasminogen activator (t-PA) release leading to endothelial fibrinolytic function [246,247]. Consequently several studies have indicated that the renoprotective of these drugs is independent of their antihypertensive effect [229].…”