Extracellular Nucleotides ATP and UTP Induce a Marked Acute Release of Tissue-type Plasminogen Activator In Vivo in Man

Hrafnkelsdóttir, Thórdís; Erlinge, David; Jern, Sverker

doi:10.1055/s-0037-1615762

Cited by 45 publications

(46 citation statements)

References 29 publications

(35 reference statements)

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“…[15][16][17][18] In brief, the subjects attended the laboratory in the morning after an overnight fast. Patients withheld all medical treatment on the study day.…”

Section: Methodsmentioning

confidence: 99%

Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients With Chronic Kidney Disease and Hypertension

et al. 2004

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Abstract-We have shown that the capacity for local release of tissue-type plasminogen activator (tPA) from the vascular endothelium is impaired in patients with primary hypertension. Because this response is an important protective mechanism against intravascular clotting, we investigated whether this system is also defective in patients with advanced chronic kidney disease and hypertension. Nine nondiabetic nonsmoking men with chronic kidney disease (glomerular filtration rate 11 to 28 mL/minϫ1.73 m 2 ; aged 33 to 75 years) were compared with age-matched healthy controls. Intraarterial infusions of desmopressin, methacholine, and sodium nitroprusside were given locally in the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography and blood collected repeatedly during the desmopressin infusion for determination of stimulated net and total cumulated release of tPA. The maximal release rate of active tPA (PϽ0.05) and the capacity for acute tPA release were markedly impaired in the renal patients as compared with healthy subjects (ANOVA, Pϭ0.013). Accordingly, the accumulated release of tPA was 1905 (SEM 366) and 3387 (718) ng/L tissue, respectively (PϽ0.05). However, there were no significant differences in vasodilator responses between the groups. Thus, patients with advanced chronic kidney disease and hypertension have a markedly impaired capacity for acute release of tissue plasminogen activator, despite preserved endothelium-dependent vasodilation. This defect may contribute to a defective local defense against arterial thrombosis.

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“…[15][16][17][18] In brief, the subjects attended the laboratory in the morning after an overnight fast. Patients withheld all medical treatment on the study day.…”

Section: Methodsmentioning

confidence: 99%

Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients With Chronic Kidney Disease and Hypertension

et al. 2004

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“…Lastly, although we focused our functional measures and discussion to the control of vasomotor tone, it should not be ignored that ATP is extremely multifarious in its vascular effects 22 by containing potent antiadhesive 23 and anticoagulative properties, 24 in addition to vasomotor effects. Thus, the fundamental observation that aged humans demonstrate low [ATP] during hypoxemia should not be discounted.…”

Section: ) Intravascular Atp Reflects That Released From Working Musmentioning

confidence: 99%

The Age-Old Tale of Skeletal Muscle Vasodilation: New Ideas Regarding Erythrocyte Dysfunction and Intravascular ATP in Human Physiology

Dinenno

Kirby

2012

Circulation Research

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“…thrombin and FVa as well as bradykinin and plateletactivating factor are potent inducers of t-PA release [42,43,46,47]. The same holds true for substances formed during tissue ischemia, and possibly ischemia per se [48][49][50][51][52]. Hereby, regulated release of t-PA may act as an important counterregulatory mechanism to prevent formation of occlusive intraluminal thrombi if a clotting process is initiated.…”

Section: Regulation Of Intravascular Fibrinolysis In Vivomentioning

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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Extracellular Nucleotides ATP and UTP Induce a Marked Acute Release of Tissue-type Plasminogen Activator In Vivo in Man

Cited by 45 publications

References 29 publications

Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients With Chronic Kidney Disease and Hypertension

Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients With Chronic Kidney Disease and Hypertension

The Age-Old Tale of Skeletal Muscle Vasodilation: New Ideas Regarding Erythrocyte Dysfunction and Intravascular ATP in Human Physiology

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

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