| 1. |
- Hrafnkelsdottir, Thórdís, et al.
(författare)
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Extracellular nucleotides ATP and UTP induce a marked acute release of tissue-type plasminogen activator in vivo in man
- 2001
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 85:5, s. 875-881
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular nucleotides such as ATP and UTP are released by activation of platelets and ischemic tissue injury. The aim of the present study was to investigate whether ATP and UTP can induce acute tPA release from the vascular endothelium in vivo. Nine healthy subjects were studied in a perfused-forearm model during stepwise intraarterial infusions of ATP and UTP (10-200 nmol/min), and UTP during inhibition of prostanoid and NO synthesis by indomethacin and L-NMMA. ATP and UTP induced a similar and marked stimulation of forearm tPA release which increased 11- and 18-fold above baseline (p < or =0.01 for both) in conjunction with pronounced vasodilation. Neither the acute tPA release nor the vasodilation could be abrogated by NO and prostanoid synthesis inhibition. The similar effect of ATP and UTP suggests that P2Y rather than adenosine receptors mediate the response. Release of extracellular nucleotides in ischemic tissue may induce a pronounced activation of the endogenous fibrinolytic system.
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| 2. |
- Hrafnkelsdottir, Thordis, 1965, et al.
(författare)
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Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension
- 2004
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Ingår i: Hypertension. - 1524-4563. ; 44:3, s. 300-4
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Tidskriftsartikel (refereegranskat)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/min x 1.73 m2; 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 (P<0.05) and the capacity for acute tPA release were markedly impaired in the renal patients as compared with healthy subjects (ANOVA, P=0.013). Accordingly, the accumulated release of tPA was 1905 (SEM 366) and 3387 (718) ng/L tissue, respectively (P<0.05). 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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| 3. |
- Hrafnkelsdottir, Thordis, 1965
(författare)
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Local regulation of the endogenous fibrinolytic system in man
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (tPA). The endothelium synthesises and stores tPA and regulated release of the enzyme is an important mechanism for removal of fibrin from blood vessels. Plasminogen activator inhibitor type-1 (PAI-1) is the main inhibitor of tPA. The aim of the present thesis was to study how the local availability of free tPA is regulated under baseline conditions and during stimulated tPA release, to explore the potential role of extracellular nucleotides as potential mediators of tPA release in tissue injury and ischaemia, and to analyse if the capacity for tPA is decreased in hypertension and advanced chronic renal failure, and if so which mechanism may be involved.The studies were performed in 115 healthy subjects, seven patients with essential hypertension, and nine patients with advanced chronic renal failure. The release of tPA and PAI-1 was studied in a perfused-forearm model, at baseline and during stimulation with sodium nitroprusside, methacholine, desmopressin, or the extracellular nucleotides ATP and UTP. Also, the synthesis and secretion of tPA were studied in human conduit vessels perfused with high versus low intraluminal pressure ex vivo. During the morning hours the fibrinolytic activity increased secondary to an increase in the endothelial release of tPA and a decrease in the overall availability of its inhibitor PAI-1. The capacity for stimulated tPA release was not predicted from either plasma concentrations of the activator or its inhibitor, or from the basal release rate of these proteins. The local availability of free active tPA during stimulation of tPA release was dependent on the tPA release rate and not the inflow/release of inhibitors (PAI-1). The extracellular nucleotides ATP and UTP were found to induce regulated tPA release, which in the case of UTP was independent of NO and prostaglandin synthesis. Nucleotide stimulated tPA release may be a potential mechanism for activation of the thromboprotective programme.The capacity for regulated tPA release was found to be markedly impaired in patients with hypertension and advanced chronic renal failure. A potential mechanism is that high blood pressure in it self impairs regulated tPA release, as high intraluminal perfusions pressure inhibited tPA synthesis and release in endothelial cells ex vivo.In conclusion, these findings support the hypothesis that regulated tPA release is the major determinant of the local availability of active tPA. It was therefore of interest to find the capacity for stimulated tPA release to be reduced in patients with hypertension and advanced chronic renal failure, an impairment that potentially increases the susceptibility for atherothrombosis.
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| 4. |
- Hrafnkelsdottir, Thordis, 1965, et al.
(författare)
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Regulation of local availability of active tissue-type plasminogen activator in vivo in man
- 2004
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Ingår i: J Thromb Haemost. - 1538-7933. ; 2:11, s. 1960-8
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Tidskriftsartikel (refereegranskat)abstract
- Free, biologically active tissue-type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI-1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused-forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6- and 12-fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r = 0.102, ns to r = 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI-1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI-1 or tPA. Despite a molar excess of PAI-1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.
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| 5. |
- Nilsson, Torun, et al.
(författare)
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Forearm blood flow responses to neuropeptide Y, noradrenaline and adenosine 5'-triphosphate in hypertensive and normotensive subjects
- 2000
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Ingår i: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 9, s. 126-131
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY), noradrenaline (NA) and adenosine 5'-triphosphate (ATP) are important co-transmitters in the sympathetic nervous system, which has a central role in cardiovascular control. In order to evaluate if hypertension is associated with alterations in vascular responses to sympathetic co-transmitters we studied the effects of intra-arterial infusion of NPY, NA and ATP on forearm blood flow. Blood flow was measured by venous occlusion plethysmography in six hypertensive (mean arterial blood pressure (MAP) 113 +/- 4 mmHg) and six matched normotensive subjects (MAP 97 +/- 3 mmHg). NPY and NA significantly reduced forearm blood flow, while a powerful increase was seen with ATP. Forearm vascular resistance, calculated as MAP divided by forearm blood flow, was significantly increased by NPY and NA and strongly reduced by ATP. There was no difference between hypertensive and normotensive subjects in response to either transmitter. In conclusion, vascular reactivity to intra-arterial administration of NPY, NA and ATP seems to be intact in hypertensive patients without metabolic aberrations.
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