Pharmacological stimulation of t-PA release in rats

Klöcking, H.-P.

doi:10.1016/0268-9499(90)90354-m

Cited by 10 publications

(10 citation statements)

References 6 publications

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“…12 Many factors-such as thrombin, fibrin, bradykinin, histamine, platelet activating factor, DDAVP, and the calcium ionophore A23187-are known to induce the release of vWf from EC in vitro and in vivo. [5][6][7][8][9][10][11]14,15,19,32 A majority of these factors also induce the acute release of t-PA. These observations suggest that t-PA and vWf are stored either in the same granules or in distinct granules that respond to similar stimuli.…”

Section: Discussionmentioning

confidence: 99%

Storage of Tissue-Type Plasminogen Activator in Weibel-Palade Bodies of Human Endothelial Cells

Rosnoblet¹,

Vischer²,

Gerard³

et al. 1999

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Abstract-Tissue-type plasminogen activator (t-PA) is acutely released by endothelial cells. Although its endothelial storage compartment is still not well defined, t-PA release is often accompanied by release of von Willebrand factor (vWf), a protein stored in Weibel-Palade bodies. We investigated, therefore, whether t-PA is stored in these secretory organelles. Under basal culture conditions, a minority of human umbilical vein endothelial cells (HUVEC) exhibited immunofluorescent staining for t-PA, which was observed only in Weibel-Palade bodies. To increase t-PA expression, HUVEC were infected with a t-PA recombinant adenovirus (AdCMVt-PA issue-type plasminogen activator (t-PA) is a key enzyme for the removal of incipient thrombi in the vascular system, and recombinant t-PA is now widely used for the thrombolytic therapy of myocardial infarction. Endothelial cells (EC) are the main source for plasma t-PA. 1-4 Although a variety of stimuli such as venous occlusion, exercise, or injection of vasoactive substances are known to acutely increase plasma levels of t-PA, the precise mechanisms responsible for this increase are poorly defined. They may involve an acute release of t-PA from EC, variations in the rate of production of t-PA by EC, or changes in the clearance rate. 5,6 Several in vivo and ex vivo studies give clear evidence for the occurrence of acute release of t-PA. Experimental induction of disseminated intravascular coagulation in chimpanzees or baboons results in a 50-fold increase in t-PA plasma levels within a few minutes. 7,8 The rapidity and the magnitude of the increase in the t-PA concentration, as well as the rapid return to normal levels, are consistent only with a massive release of t-PA from storage pools. The findings that injection of vasoactive agents such as thrombin or calcium ionophore leads to an acute increase of t-PA in isolated vascular systems are also consistent with an endothelial t-PA storage pool. 9 -11

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Section: Discussionmentioning

confidence: 99%

Storage of Tissue-Type Plasminogen Activator in Weibel-Palade Bodies of Human Endothelial Cells

Rosnoblet¹,

Vischer²,

Gerard³

et al. 1999

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“…Catecholamines are known to enhance systemic levels of t-PA 9,10,28 as well as to induce regulated release of t-PA in the human forearm, 6 rat hind leg, 29,30 and pig ear vascular beds 31 and thus have to be considered one of the candidate mediators of the response to sympathetic stimulation. In the present study, we therefore also investigated the effect of local infusion of the ␣-and ␤-adrenergic agonists phenylephrine and isoprenaline.…”

Section: Björkman Et Al Sympathetic Stimulation Induces T-pa Releasementioning

confidence: 99%

Cardiac Sympathetic Nerve Stimulation Triggers Coronary t-PA Release

Björkman

Jern

2003

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Objective-This study was undertaken to determine whether stimulation of sympathetic cardiac nerves induces release of the thrombolytic enzyme tissue-type plasminogen activator (t-PA) in the coronary vascular bed. Methods and Results-Anesthetized pigs were studied in an open chest model. Bilateral vagotomy was performed, and sympathetic cardiac nerves were activated by electrical stimulation (1 and 8 Hz). To evaluate possible mediating effects of increased heart rate and enhanced local blood flow, tachycardia was induced by pacing and hyperemia by local infusion of sodium nitroprusside and clevedipine. Furthermore, to study the effects of ␣-and ␤-adrenergic receptor stimulation, phenylephrine and isoprenaline were infused locally. In response to low-and high-frequency sympathetic stimulation, mean coronary net release of total t-PA increased approximately 6-and 25-fold, respectively. Active t-PA showed a similar response pattern. Neither tachycardia nor coronary hyperemia stimulated t-PA release. In contrast, ␤-adrenergic stimulation by isoprenaline induced an approximately 6-fold increase in coronary t-PA release, whereas no significant change in release rates occurred in response to ␣-adrenergic stimulation by phenylephrine. The endothelium continuously secretes t-PA by a constitutive pathway. In addition, t-PA can be rapidly released from endothelial stores in response to various stimuli by a regulated pathway. Such an acute release of t-PA is a key event in initiating an endogenous fibrinolytic response, 2 which in turn may result in endogenous removal of thrombi. Unfortunately, however, regulated release of t-PA in vivo cannot be determined by measurements of systemic plasma levels of t-PA, because plasma t-PA is sensitive to alterations in hepatic blood flow. [3][4][5] To overcome this problem, we adapted the human perfused-forearm model to study local t-PA release 6,7 and demonstrated that both mental stress and local infusion of norepinephrine induce an acute release of t-PA in the forearm vascular bed. 6,8 It is well-known that sympathetic stimulation induces activation of procoagulant mechanisms on the systemic level. 9,10 It is therefore of interest to investigate if an acute t-PA release can be induced also in the coronary circulation by sympathetic activation, because such a response might oppose stress-induced procoagulant activation and thereby protect against clot formation. In the present study, we investigated the effect of sympathetic stimulation on coronary t-PA release in a pig model by determining coronary release of t-PA during electrical stimulation of cardiac sympathetic nerves. If such a stimulatory effect could be demonstrated, a second aim was to investigate if the accompanying hemodynamic alterations that occur during sympathetic stimulation (ie, tachycardia and coronary hyperemia) as such could mediate the response. We also examined the effects of local infusion of the unselective ␤-adrenergic agonist isoprenaline and the ␣-adrenergic agonist phenylephrine on coronary t-PA release. C...

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“…During physiological conditions, circulating plasma levels of this active enzyme are expected to be low to ensure haemostasis, but in the case of an adverse event, such as thrombosis, a rapid up‐regulation appears within minutes. This is facilitated through an inducible acute release of t‐PA from an endothelial storage pool ( 1), for which response several agonists have been identified ( 2–10). Our previous data describe a heterogeneity of t‐PA release and uptake responses in various vascular beds ( 11–13), which points to the crucial role of the local capacity for acute t‐PA release in the anti‐thrombotic defence.…”

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confidence: 99%