Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin

Pretorius, Mias; Rosenbaum, David A.; Vaughan, Douglas E.; Brown, Nancy J.

doi:10.1161/01.cir.0000046268.59922.a4

Cited by 88 publications

(75 citation statements)

References 48 publications

(57 reference statements)

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“…FBF was measured using strain-gauge venous occlusion plethysmography (D.E. Hokanson, Bellevue, WA), as described previously, 14,52 at each of the six timepoints outlined above. FBF was measured in milliliters per 100 ml of volume tissue per minute.…”

Section: Study Protocolmentioning

confidence: 99%

“…On the one hand, bradykinin causes vasodilation and stimulates the release of t-PA from the vascular endothelium via bradykinin B 2 receptor-dependent mechanisms, and infused bradykinin inhibits platelet aggregation in healthy subjects. [12][13][14] On the other hand, bradykinin also stimulates activation of nuclear factor B and cytokine expression via the B 2 receptor. 15,16 Understanding the contribution of endogenous bradykinin to the inflammatory response to hemodialysis has important implications for the prevention of atherothrombotic events.…”

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confidence: 99%

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Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Marney¹,

Ma²,

Luther

et al. 2009

Journal of the American Society of Nephrology

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Oxidative stress and inflammation predict cardiovascular events in chronic hemodialysis patients. Hemodialysis activates the kallikrein-kinin system, increasing bradykinin. Bradykinin promotes inflammation but also stimulates endothelial release of tissue-plasminogen activator and inhibits platelet aggregation. Understanding the detrimental and beneficial effects of endogenous bradykinin during hemodialysis has implications for the treatment of cardiovascular disease in the hemodialysis population. To test the hypothesis that bradykinin contributes to the inflammatory and fibrinolytic responses to dialysis, we conducted a double-blind, randomized, placebo-controlled crossover study comparing the effect of the bradykinin B 2 receptor blocker HOE-140 with vehicle on markers of oxidative stress, inflammation, fibrinolysis, and coagulation in nine hemodialysis patients without coronary artery disease. Bradykinin receptor antagonism did not affect the mean arterial pressure or heart rate response to dialysis. Monocyte chemoattractant protein 1 (MCP-1) peaked postdialysis; HOE-140 blunted the increase in MCP-1 (5.9 Ϯ 5.9 versus 25.6 Ϯ 20.1 pg/ml, P ϭ 0.01). HOE-140 also abolished the increase in plasminogen activator inhibitor 1 (PAI-1) antigen observed at the end of dialysis. In contrast, HOE-140 significantly accentuated the effect of dialysis on F 2 -isoprostanes and P-selectin. Taken together, these results suggest that endogenous bradykinin contributes to increases in MCP-1 and PAI-1 antigen after hemodialysis via its B 2 receptor. Factors that increase the production of bradykinin or decrease its degradation may enhance the inflammatory response to hemodialysis.

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Section: Study Protocolmentioning

confidence: 99%

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confidence: 99%

Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Marney¹,

Ma²,

Luther

et al. 2009

Journal of the American Society of Nephrology

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“…2,4 ACE inhibition alters fibrinolysis by decreasing angiotensin II formation, a potent stimulus for PAI-1 expression, 5 and also by reducing the enzymatic degradation of bradykinin, a potent stimulus of tPA release. 19,20 ACEIs have been shown to reduce circulating PAI-1 antigen in patients with risk factors for coronary artery disease 9,13,21 or after myocardial infarction. 11,22 In addition, ACE inhibition prevents the increase in PAI-1 after thrombolysis.…”

Section: Pretorius Et Al Ace Inhibition Pai-1 and Cardiopulmonary Bmentioning

confidence: 99%

“…CPB stimulates the kallikrein-kinin system, increasing bradykinin concentrations 10-to 20-fold. 23,24 Because bradykinin stimulates endothelial tPA release, 19,20 decreased bradykinin clearance during ACE inhibition would be expected to increase tPA. Thus, the net effect of ACE inhibition in patients undergoing elective CABG requiring CPB was to increase fibrinolytic activity by decreasing PAI-1 antigen and increasing tPA antigen.…”

Section: Pretorius Et Al Ace Inhibition Pai-1 and Cardiopulmonary Bmentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibition Alters the Fibrinolytic Response to Cardiopulmonary Bypass

et al. 2003

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Background-Increased plasminogen activator inhibitor-1 (PAI-1) concentrations after coronary artery bypass grafting (CABG) are associated with increased risk of vein graft occlusion. Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG. Methods and Results-We measured the effects of cardiopulmonary bypass (CPB) on PAI-1 antigen and tissue-type plasminogen activator (tPA) antigen and activity in 31 patients taking an ACE inhibitor (ACEI) who were randomized to continue ACEI until the morning of surgery (ACEI group, nϭ19) or to discontinue it 48 hours before surgery (No-ACEI group, nϭ12). Arterial blood samples were taken at baseline before CPB, twice during CPB, after separation from CPB, and on postoperative day 1 (POD1). CPB caused an early decrease in PAI-1 antigen, followed by an increase in PAI-1 antigen on POD1 (PϽ0.001 for effect of time). ACE inhibition attenuated the increase in PAI-1 antigen such that both PAI-1 antigen on POD1 (Pϭ0.013) and the change in PAI-1 antigen from baseline to POD1 (Pϭ0.009) were higher in the No-ACEI group (from 17.0Ϯ5.0 to 48.7Ϯ8.8 ng/mL) versus the ACEI group (from 19.9Ϯ3.4 to 33.1Ϯ6.2 ng/mL). There was no significant difference between the 2 groups in intraoperative tPA activity (Pϭ0.259); however, the increase in tPA activity was significantly greater in the ACEI group than in the No-ACEI group (Pϭ0.030). Conclusions-Preoperative

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“…22 In addition, ACE inhibition potentiates bradykinin-stimulated t-PA release to a greater extent in premenopausal women than in postmenopausal women and in either group of women compared with age-matched men, 23 suggesting that estrogen may modulate the effect of ACE inhibition on bradykininstimulated t-PA release. This study tested the hypothesis that 17␤-estradiol enhances t-PA release in the presence of ACE inhibition in young postmenopausal women.…”

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17β-Estradiol Increases Basal but Not Bradykinin-Stimulated Release of Active t-PA in Young Postmenopausal Women

et al. 2008

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Abstract-Angiotensin-converting enzyme inhibition potentiates basal and bradykinin-stimulated tissue-type plasminogen activator (t-PA) release to a greater extent in women than in men. This study tested the hypothesis that 17␤-estradiol enhances the effect of angiotensin-converting enzyme inhibition on t-PA release in young postmenopausal women. We conducted a double-blind, prospective, crossover study in 14 young postmenopausal women (mean age 48.2Ϯ2.3 years) who were randomized to receive 17␤-estradiol (1 mg/d) or matching placebo for 4 weeks. At the end of each treatment period, we measured the effect of intraarterial infusion of bradykinin, methacholine, and nitroprusside on forearm blood flow and net t-PA release, before and during intraarterial enalaprilat (0.33 g/min/100 mL forearm volume Key Words: estradiol Ⅲ angiotensin-converting enzyme inhibition Ⅲ postmenopausal women Ⅲ plasminogen activator Ⅲ bradykinin E strogen deficiency of menopause causes vascular and metabolic changes that increase the risk for cardiovascular disease. 1,2 In contrast to observational studies that suggest that hormone replacement therapy (HRT) reduces the risk of coronary heart disease (CHD), 3-5 recent randomized controlled trials indicate that treatment with conjugated estrogen plus progestin increases the risk of pulmonary emboli, CHD, and stroke, whereas treatment with conjugated estrogen alone increases risk of stroke without affecting embolic events or risk of CHD. 6 -8 This discrepancy in results has been attributed to the type of HRT used, the timing of intervention of HRT after menopause, 9,10 or the route of administration. 11 For example, the Heart and Estrogen/progestin Replacement Study (HERS) 8 and the Women's Health Initiative (WHI) 6,7 study assessed the effect of treatment with conjugated equine estrogens, a mixture of estrogens extracted from horse urine that also contains progestins and androgens, whereas estradiol is the major endogenous estrogen. 12 Differences in the outcomes of epidemiological studies and clinical trials are best interpreted in the context of an understanding of the biological effects of estrogen. On the one hand, oral HRT increases circulating fibrin split products (FSP), concentrations of inflammatory cytokines, and C-reactive protein. [13][14][15] On the other, estradiol exerts many salutary effects on the vasculature, including improving endothelial-dependent vasodilation, 16 decreasing fibrinogen and plasminogen activator inhibitor (PAI)-1 (PAI-1), [17][18][19] increasing the secretion of nitric oxide from intact platelets, 20 and attenuating platelet-derived growth factor (PDGF) receptor-activated smooth muscle cell migration and proliferation. 21 HRT decreases circulating t-PA antigen in parallel with PAI-1 antigen, to which it is complexed. Circulating t-PA antigen does not reflect the capacity of the vasculature to release t-PA, however, and the effect of HRT or estrogen on endothelial fibrinolytic function has not been studied exten-

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Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin

Cited by 88 publications

References 48 publications

Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Angiotensin-Converting Enzyme Inhibition Alters the Fibrinolytic Response to Cardiopulmonary Bypass

17β-Estradiol Increases Basal but Not Bradykinin-Stimulated Release of Active t-PA in Young Postmenopausal Women

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