Release of Tissue-Type Plasminogen Activator in Response to Muscarinic Receptor Stimulation in Human Forearm

Jern, Sverker; Selin, Lena; Bergbrant, A; Jern, Christina

doi:10.1055/s-0038-1648920

Cited by 57 publications

(38 citation statements)

References 24 publications

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“…18 Our finding that this com- pound failed to stimulate t-PA release reinforces the concept that the relationship between NO and fibrinolysis mainly occurs within endothelial cells. Although evidence is concordant on the possibility to release t-PA by receptor-operated agonists, including methacholine 15,17 and bradykinin, 16,19 results with acetylcholine are discordant. 16,19 However, a likely explanation is the short duration of acetylcholine infusion in negative articles (5 minutes per dose) 16 as compared with our experimental conditions (15 minutes per dose).…”

Section: Discussionmentioning

confidence: 99%

“…Because sodium nitroprusside administration, despite a similar blood flow increment, had no such effect, these results confirm that the t-PA release is an endothelial property not dependent on flow increase. [15][16][17] Worth noting, sodium nitroprusside is an exogenous NO donor, acting directly on vascular smooth muscle cells. 18 Our finding that this com- pound failed to stimulate t-PA release reinforces the concept that the relationship between NO and fibrinolysis mainly occurs within endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Nitric Oxide Modulates Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

et al. 2007

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We evaluated the possible role of NO in modulating tissue plasminogen activator (t-PA) release in the forearm microcirculation of normotensive subjects and hypertensive patients. Essential hypertensive patients are characterized by endothelial dysfunction because of a reduced NO availability and also show an impaired t-PA release. In healthy volunteers and essential hypertensive patients, we studied local t-PA release and forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.45 and 1.5 microg/100 mL/min) and of sodium nitroprusside (0.5 and 1.0 microg/100 mL/min), an endothelium-dependent and -independent agonist, respectively. Acetylcholine was also repeated in the presence of intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-l-arginine (100 microg/100 mL/min). In normotensive subjects, vasodilation to acetylcholine was blunted by N(G)-monomethyl-l-arginine. In these subjects, acetylcholine infusion induced a significant, dose-dependent increase in net forearm t-PA release. N(G)-monomethyl-l-arginine significantly reduced basal t-PA release, as well as acetylcholine-induced t-PA release. In essential hypertensive patients, vasodilation to acetylcholine was reduced as compared with controls and resistant to N(G)-monomethyl-l-arginine. In contrast to what was observed in healthy control subjects, in hypertensive patients, acetylcholine had no effect on t-PA release. Similarly, N(G)-monomethyl-l-arginine failed to modify either the tonic or the agonist-induced t-PA release. Both tonic and agonist-induced release of NO are directly involved in t-PA release by endothelial cells. Essential hypertension, characterized by a reduction in tonic and stimulated NO availability, is also associated with impaired capacity of t-PA release, suggesting a major role of impaired NO availability in worsening both vasodilation and t-PA release.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Modulates Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

et al. 2007

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“…The endothelial release of t-PA may be regulated in part by nitric oxide (Jern et al 1994;Newby et al 1998). Hoetzer et al (2003a) found a dose dependent increase in t-PA antigen net release in response to bradykinin.…”

Section: Fibrinolytic Potentialmentioning

confidence: 99%

“…This may not be surprising since both endothelial function and Wbrinolytic potential are at least partially regulated by nitric oxide (Jern et al 1994;Newby et al 1998) and aerobic exercise is thought to improve nitric oxide metabolism (Kingwell et al 1997). While resistance exercise is strongly recommended as part of a regular exercise program, little is known about the eVects of resistance training on either endothelial function or Wbrinolysis.…”

Section: Introductionmentioning

confidence: 99%

Fibrinolytic markers and vasodilatory capacity following acute exercise among men of differing training status

et al. 2007

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We evaluated the effect of differing physical activity patterns on fibrinolysis and vasodilatory capacity using a cross-sectional design with 16 endurance-trained (ET) (mean+/-SE) (28+/-6 years), 14 resistance-trained (RT) (28+/-7 years), and 10 untrained (UT) (26+/-7 years) men. t-PA and PAI-1 activity and t-PA antigen were measured before and after a maximal treadmill test (VO2peak). Vasodilatory capacity was assessed using strain-gauge plethysmography on the forearm following reactive hyperemia (RH) before and after the treadmill test. The ET group had a smaller body mass index (BMI) (22.8+/-0.5 ET, 26.4+/-0.4 RT, 25.1+/-0.8 UT kg m(-2)) (P<0.05) and a greater VO2peak (57+/-1 ET, 42+/-2 RT, 45+/-2 UT mL min(-1) kg(-1)) (P<0.05). Peak vasodilatory capacity (29.7+/-2 ET, 32.0+/-2 RT, 27.4+/-2 UT mL min(-1) 100 mL of tissue) was similar between groups before and after exercise. Area under the curve for forearm blood flow was greater following acute exercise (212 vs. 122, P<0.05), again with no differences between groups. t-PA activity and antigen increased following maximal exercise in all groups (P<0.0001), with no group differences. PAI-1 activity decreased the least in RT after exercise (70% decrease vs. 86% ET and 82% UT; P<0.05). The change in t-PA activity with exercise was not related to exercise-induced change in overall vasodilatory capacity. These findings demonstrate that in healthy young men different physical activity patterns do not appear to impact the exercise-induced changes in fibrinolysis or vasodilatory capacity.

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“…Thus, the systemic levels of tPA may not reflect the local profibrinlolytic capacity in terms of availability of active tPA at the organ level. In 1994 we therefore described a human in vivo model, in which the release of fibrinolytic proteins from the endothelium could be studied in man [7–9].…”

Section: Introductionmentioning

confidence: 99%

Regulation of local availability of active tissue‐type plasminogen activator in vivo in man

Hrafnkelsdóttir

Guðnason

Wall

et al. 2004

Journal of Thrombosis and Haemostasis

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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 ¼ 0.102, ns to r ¼ 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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Release of Tissue-Type Plasminogen Activator in Response to Muscarinic Receptor Stimulation in Human Forearm

Cited by 57 publications

References 24 publications

Nitric Oxide Modulates Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

Nitric Oxide Modulates Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

Fibrinolytic markers and vasodilatory capacity following acute exercise among men of differing training status

Regulation of local availability of active tissue‐type plasminogen activator in vivo in man

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