Comparative Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Antagonism on Plasma Fibrinolytic Balance in Humans

Abstract

Abstract-Angiotensin-converting enzyme (ACE) inhibition significantly decreases plasminogen activator inhibitor-1 (PAI-1) without altering tissue plasminogen activator (tPA) during activation of the renin-angiotensin-aldosterone system in humans. Because ACE inhibitors and angiotensin II type 1 (AT 1 ) receptor antagonists differ in their effects on angiotensin II formation and bradykinin degradation, the present study compared the effect of equivalent hypotensive doses of an ACE inhibitor and AT 1 antagonist on fibrinolytic balance. Plasma PAI-1 antigen, tPA antigen, plasma renin activity, and aldosterone were measured in 25 normotensive subjects (19 white, 6 black; 14 men, 11 women; mean age 38.5Ϯ1.8 years; mean body mass index 25.3Ϯ0.7 kg/m 2 ) during low salt intake alone (10 mmol Na/d), low salt intake ϩ quinapril (40 mg PO bid), and low salt intake ϩ losartan (50 mg PO bid). Compared with low salt alone (systolic blood pressure [BP] 118.8Ϯ2.2 mm Hg), both quinapril (106.3Ϯ2.5 mm Hg, PϽ0.001) and losartan (105.4Ϯ2.8 mm Hg, PϽ0.001) reduced BP. No statistical difference was found between quinapril and losartan in their BP lowering effect. Losartan (Pϭ0.009), but not quinapril, lowered heart rate. Both drugs significantly lowered aldosterone (PϽ0.001 versus low salt alone for each); however, this effect was significantly greater for quinapril than for losartan (PϽ0.001 for quinapril versus losartan). Treatment with quinapril, but not with losartan, was associated with a decrease in both PAI-1 antigen (Pϭ0.03) and activity (Pϭ0.018). PAI-1 activity was lower during treatment with quinapril than with losartan (Pϭ0.015). The average PAI-1 antigen concentration was 13.0Ϯ2.0 ng/mL during low salt alone, 10.5Ϯ1.6 ng/mL during quinapril treatment, and 12.3Ϯ2.1 ng/mL during losartan treatment. In contrast, plasma tPA antigen concentrations were reduced during treatment with losartan (Pϭ0.03) but not with quinapril. This study provides the first evidence that ACE inhibitors and AT 1 antagonists differ in their effects on fibrinolytic balance under conditions of activation of the renin-angiotensin-aldosterone system. Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences. (Hypertension. 1999;34:285-290.) Key Words: angiotensin II Ⅲ renin Ⅲ plasminogen activators A ctivation of the renin-angiotensin-aldosterone system (RAAS) has been associated with an increased risk of ischemic cardiovascular events independent of effects on blood pressure (BP). 1,2 Conversely, interruption of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor decreases progression of atherosclerosis in animal models 3,4 and appears to reduce the risk of recurrent myocardial infarction (MI) in patients with left ventricular dysfunction. 5,6 The mechanisms through which activation of the RAAS increases or ACE inhibition decreases the risk of ischemic cardiovascular events in selected populations is not known. One...

Effect of delapril–manidipine combination vs irbesartan–hydrochlorothiazide combination on fibrinolytic function in hypertensive patients with type II diabetes mellitus

“…In this study irbesartan monotherapy did not significantly affect the fibrinolytic balance, thus confirming previous findings. [22][23][24][25][26][27] Possible explanations for the dissimilar effect of ACE inhibition and Ang II antagonism on PAI-1 levels might be that: (a) the endothelial receptors that mediate PAI-1 expression in response to Ang II are not type I receptor subtypes, but rather the AT4 receptors, which specifically bind to the hexapeptide 3-8 fragment of Ang II, indicated as Ang IV; 41 (b) unlike ACE Inhibitors, Ang II antagonists have no effect on the endogenous kinins. 42 The addition of hydrochlorothiazide to irbesartan monotherapy produced a significant increase in PAI-1 activity, which confirms previous observations.…”

“…13 Variable effects have been reported for diuretics 14,15 and b-blockers, 16,17 whereas Ca-antagonists seem to be associated with an increase in plasma t-PA activity. 18,19 ACE inhibitors have been demonstrated to reduce plasma levels of PAI-1, [20][21][22][23][24] whereas contrasting results have been reported on the effects of the angiotensin II (Ang II) antagonists. [22][23][24][25][26][27] The aim of the present study was to evaluate the effects on plasma PAI-1 and t-PA activities of the combination of delapril, a nonsulphydryl, nonprolinic, lipophilic ACE inhibitor, with high affinity for the C-terminal site of ACE 28 with manidipine, a second-generation, lipophilic dihydropyridine Caantagonist, with good efficacy/tolerability profile 29 as compared to the combination of the Ang II AT1 receptor antagonists irbesartan with hydrochlorothiazide in the treatment of hypertensive patients with type II diabetes mellitus, a population with a great impairment of the fibrinolytic function.…”

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

“…Certainly, ACE inhibitors and ARB differ in their effects on fibrinolytic balance. 21 As reviewed by Felmeden and Lip, 22 ACE inhibitors reduce degradation of bradykin in to inactive metabolites, resulting in increased activity of t-PA, which is not affected by the angiotensin type-1 receptor. Moreover, angiotensin II increases PAI-1 expression via angiotensin type-4 receptors.…”

“…33,34 The present (and previous) work suggests that the ACE inhibitors have a better effect on fibrinolytic function than ARB. 18,21,23 Thus, the question is not should we treat (where the answer is clear) but how to treat hypertension, and importantly, are we content with lowering blood pressure alone, or should we be asking something more from the antihypertensive drugs we use.…”

The impact of angiotensin II receptor blockade and the DASH diet on markers of endogenous fibrinolysis

“…However, data regarding the effect of angiotensinconverting enzyme (ACE) inhibition and AII receptor blockade on fibrinolytic parameters are inconsistent. [14][15][16][17] A reduction in t-PA antigen levels could be important because elevated t-PA antigen levels have been associated with an increased risk of myocardial infarction and stroke, and in epidemiologic studies t-PA antigen is a stronger predictor of adverse events than PAI-1. [18][19][20] In normotensive persons given a salt depleted diet, losartan reduced t-PA antigen.…”