Impaired Capacity for Stimulated Fibrinolysis in Primary Hypertension Is Restored by Antihypertensive Therapy

Ridderstråle, Wilhelm; Ulfhammer, Erik; Jern, Sverker; Hrafnkelsdóttir, Thórdís

doi:10.1161/01.hyp.0000210540.35296.62

Cited by 37 publications

(37 citation statements)

References 45 publications

(31 reference statements)

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“…In hypertensive patients, bradykinin-induced and acetylcholine-induced tPA release was impaired, a finding in line with a well-documented reduction in endothelial fibrinolytic capacity in this clinical condition, previously demonstrated with different stimuli, including desmopressin, 27 substance P, 28 acetylcholine, 4 and epinephrine. 26 It is, however, interesting to observe that in hypertensive patients, the residual but still evident bradykinin-induced tPA release was totally resistant to L-NMMA, whereas it was blocked by sulfaphenazole.…”

Section: Discussionsupporting

confidence: 86%

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

et al. 2009

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Background-A nitric oxide-independent response, possibly mediated by hyperpolarization, regulates vascular tone, acting as a compensatory mechanism in the presence of impaired nitric oxide availability. Cytochrome P450 2C9 (CYP 2C9) is a source of endothelium-derived hyperpolarizing factors and modulates tissue-type plasminogen activator (tPA) release from endothelial cells; however, no effect of hyperpolarization on fibrinolysis has been documented in humans. We aimed to assess the effect of sulfaphenazole, a specific CYP 2C9 inhibitor, on tPA release in normotensive subjects and patients with essential hypertension. Methods and Results-tPA release was measured in the forearm microcirculation of 56 normotensivesubjects and 57 patients with essential hypertension after bradykinin (0.015 g · 100 mL Ϫ1 · min

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Section: Discussionsupporting

confidence: 86%

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

et al. 2009

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“…9 The present results show that epinephrine also participates in the modulation of local fibrinolysis via the activation of t-PA release in the microcirculation of healthy subjects. Epinephrine-induced t-PA release was blunted in hypertensive patients, a finding that strongly reinforces the concept of impaired t-PA release in essential hypertension, as reported previously with different stimuli, such as desmopressin, 6 substance P, 28 and acetylcholine. 4 This is a crucial issue because only t-PA acutely released and incorporated into the growing thrombus effectively activates plasminogen to plasmin, 29 thereby being protected from its main circulating inhibitor PAI-1.…”

Section: Giannarelli Et Al No and Adrenergic-induced T-pa Release In supporting

confidence: 89%

“…4 This is a crucial issue because only t-PA acutely released and incorporated into the growing thrombus effectively activates plasminogen to plasmin, 29 thereby being protected from its main circulating inhibitor PAI-1. 6,28 The major novel finding of the present study is the demonstration that epinephrine-induced t-PA release is mediated by the activation of the NO pathway. The inhibition of NO with L-NMMA significantly reduced basal and epinephrine-induced t-PA release in normotensive subjects, thereby confirming a positive modulating effect of NO on both tonic and stimulated t-PA release in healthy conditions.…”

Section: Giannarelli Et Al No and Adrenergic-induced T-pa Release In mentioning

confidence: 61%

Tissue-Type Plasminogen Activator Release in Healthy Subjects and Hypertensive Patients

et al. 2008

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Abstract-The relationship between adrenergic stimuli and NO in modulating tissue-type plasminogen activator (t-PA) release from endothelial cells was investigated in normotensive subjects and essential hypertensive patients. Sympathetic activation, a well-known stimulus for endogenous fibrinolysis, is also involved in the determination of cardiovascular risk in essential hypertension. However, the existence of cross-talk between adrenergic stimuli and NO availability in modulating t-PA release is not well established yet. We assessed the release of t-PA in the forearm microcirculation of 58 normotensive subjects (mean age: 47Ϯ9 years) and 44 essential hypertensive patients (mean age: 48Ϯ11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 g/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (PϽ0.05). However, inhibition of NO synthase with N G -monomethyl-L-arginine (100 g/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (PϽ0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 g/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 g/100 mL per minute). Intrabrachial isoproterenol (0.03 g/100 mL per minute) induced a significant increase in t-PA release (PϽ0.01), an effect blunted by N G -monomethyl-L-arginine (PϽ0.05). In essential hypertensive patients, the response to isoproterenol was impaired as compared with normotensive subjects and was unaffected by N G -monomethyl-L-arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by ␤-adrenoreceptors via a mechanism involving the NO pathway. Our results show an impaired adrenergic-stimulated t-PA release among essential hypertensive patients, probably mediated via a reduced NO availability. This impaired fibrinolytic activity might contribute to the increased cardiovascular risk associated with hypertension. (Hypertension. 2008;52:314-321.) Key Words: t-PA Ⅲ receptors Ⅲ adrenergic-␤ Ⅲ NO Ⅲ endothelium Ⅲ hypertension Ⅲ essential T he endogenous fibrinolytic system contributes to the maintenance of vessel patency via the cleavage of insoluble fibrin by plasmin. The activation of plasmin by tissue-type plasminogen activator (t-PA) is a physiological process that, clearing inappropriate intravascular fibrin deposition, prevents vascular atherothrombotic events. 1,2 The coagulation factors thrombin and activated factor X, acting as counterregulatory mechanisms during fibrin deposition, are considered the main stimuli for acute t-PA release from endothelial cells. 2 Thus, the vascular endothelium plays a major regulatory role in endogenous fibrinolysis. 3 One of the main mechanisms by which a healthy endothelium regulates acute release of t-PA involves the NO pathway. 4 In certain pathological conditions charact...

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“…smokers [7,8] and hypertensives [9,10]. It has, however, recently been shown, that the impairment in the latter group is reversible as it can be restored by anti-hypertensive therapy [11].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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Impaired Capacity for Stimulated Fibrinolysis in Primary Hypertension Is Restored by Antihypertensive Therapy

Cited by 37 publications

References 45 publications

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

Tissue-Type Plasminogen Activator Release in Healthy Subjects and Hypertensive Patients

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

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