Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension

Sakata, Kazuki; Shirotani, Manabu; Yoshida, Hiroshi; Urano, Tetsumei; Takada, Yumiko; Takada, Akikazu

doi:10.1016/s0002-8703(99)70368-6

Cited by 34 publications

(31 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7,17 To investigate the potential effect of hypertension on vascular PAI-1 mRNA levels in rats, we compared aortic and cardiac PAI-1 expression in the SHR with that of normotensive WKY control rats. This study demonstrated that PAI-1 expression in these vascular tissues was elevated by 2-to 5-fold in the SHR compared with WKY rats.…”

Section: Blood Pressure Of Shrs and Wky Ratsmentioning

confidence: 99%

“…8 -11 The physiological importance of the RAS in modulating PAI-1 levels is supported by in vivo studies, which have demonstrated that treatment of rats with the angiotensin-converting enzyme (ACE) inhibitor captopril suppresses the induction of PAI-1 expression in the aortic neointima induced by balloon catheter injury, 12 and a number of clinical studies, which have shown that the ACE inhibitors and the angiotensin type 1 (AT 1 ) receptor antagonist reduce plasma PAI-1 antigen and activity. 7,[13][14][15][16][17] Although these reports provide substantial evidence for an important role of the RAS in PAI-1 expression, the specific effects of angiotensin-related peptides and the role of the AT 1 receptor in regulating PAI-1 expression remain controversial.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Chen¹,

Bouchie²,

Perez³

et al. 2000

ATVB

View full text Add to dashboard Cite

Abstract-Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT 1 ) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT 1 antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg 2 -Phe 8 (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT 1 antagonist candesartan. Angiotensin Val 3 -Phe 8 (Ang IV) and angiotensin Asp 1 -Pro 7 (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (PϽ0.01), and this response was completely blocked by AT 1 receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17-and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (PϽ0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (PϽ0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT 1 receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression. Key Words: angiotensin II Ⅲ plasminogen activator inhibitor Ⅲ hypertension Ⅲ aorta Ⅲ vascular smooth muscle cells P lasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of tissue and urokinase plasminogen activators and thereby reduces the conversion of plasminogen to plasmin, an extracellular protease that mediates fibrinolysis and activates matrix metalloproteinases. 1-3 An elevated level of PAI-1, which occurs in diabetes, insulin resistance, obesity, and hypertension, has been implicated as a contributing risk factor for cardiovascular disease. 4 -7 Recent studies suggest that the renin-angiotensin system (RAS) may exert an important role in the regulation of circulating and vascular PAI-1 expression and may thereby affect the fibrinolytic balance. Reports from our laboratory and others have demonstrated that angiotensin II (Ang II) is a potent stimulator of PAI-1 mRNA and protein expression in both cultured endothelial and vascular smooth muscle cells. 8 -11 The physiological importance of the RAS in modulating PAI-1 levels is supported by in vivo studies, which have demonstrated that treatment of rats with the angiotensin-converting enzyme (ACE) inhibitor captopril suppresses the induction of PAI-1 expression in the aortic neointima induced by b...

show abstract

Section: Blood Pressure Of Shrs and Wky Ratsmentioning

confidence: 99%

mentioning

confidence: 99%

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Chen¹,

Bouchie²,

Perez³

et al. 2000

ATVB

View full text Add to dashboard Cite

show abstract

“…23 The effects of calcium antagonists on fibrinolysis have been poorly studied and conflicting data have been reported with some studies demonstrating that calcium antagonists improve 24 and others showing impairment of fibrinolytic function. 25,26 Finally, the unfavourable effect of hydrochlorothiazide on fibrinolysis has previously been observed. 23 In the study by Mugellini et al, 18 it is of note that there were no statistical differences in blood pressure-lowering efficacy between both combinations of antihypertensive drugs with no changes in the whole study period.…”

mentioning

confidence: 91%

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

Roldán¹,

Marı́n

2004

J Hum Hypertens

View full text Add to dashboard Cite

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

show abstract

“…Many other studies have demonstrated the beneficial effects of ACE-I on prothrombotic state, [12][13][14][15][16][17] as well as insulin sensitivity [58][59][60] in addition to their efficacy in normalizing elevated BP, which might result in better cardiovascular protection by these drugs. In this regard, a meta-analysis of clinical studies has shown that ACE-I but not ARB may reduce the risk of major coronary disease events.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15][16][17] The effects of ACE-Is on t-PA are more controversial, as some studies have shown increased t-PA levels, 18,19 other studies have reported decreased t-PA levels 12,20 and still others have observed unchanged t-PA levels during ACE inhibition. 13,21,22 One possible explanation for these contrasting findings might be that t-PA exists in several forms, including free active t-PA and t-PA bound to PAI-1 and other inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

et al. 2010

View full text Add to dashboard Cite

The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (À16/12.6 and À16.1/12.2 mm Hg, respectively, Po0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min À1 per kg, Po0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (Po0.05 vs. baseline, Po0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48 ± 0.16 to 0.43 ± 0.14 IU ml À1 , Po0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml À1 ) than by candesartan (+2.73 IU ml À1 , Po0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

show abstract

Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension

Cited by 34 publications

References 35 publications

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

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

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

Contact Info

Product

Resources

About

Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension

Cited by 34 publications

References 35 publications

Role of the Angiotensin AT 1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Role of the Angiotensin AT 1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

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

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

Contact Info

Product

Resources

About

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression