Published online before print June 23, 2008, doi: 10.1161/HYPERTENSIONAHA.108.111559
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(Hypertension. 2008;52:314.)
© 2008 American Heart Association, Inc.
Original Articles |
Tissue-Type Plasminogen Activator Release in Healthy Subjects and Hypertensive Patients
Relationship With β-Adrenergic Receptors and the Nitric Oxide Pathway
From the Department of Internal Medicine, University of Pisa, Pisa, Italy.
Correspondence to Chiara Giannarelli, Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. E-mail c.giannarelli{at}int.med.unipi.it
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Abstract |
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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: 47±9 years) and 44 essential hypertensive patients (mean age: 48±11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 µg/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (P<0.05). However, inhibition of NO synthase with NG-monomethyl-L-arginine (100 µg/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (P<0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 µg/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 µg/100 mL per minute). Intrabrachial isoproterenol (0.03 µg/100 mL per minute) induced a significant increase in t-PA release (P<0.01), an effect blunted by NG-monomethyl-L-arginine (P<0.05). In essential hypertensive patients, the response to isoproterenol was impaired as compared with normotensive subjects and was unaffected by NG-monomethyl-L-arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by β-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.
Key Words: t-PA • receptors • adrenergic-β • NO • endothelium • hypertension • essential
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Introduction |
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The 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 characterized by reduced NO availability, such as essential hypertension, in which an impaired endothelium-dependent vasodilation occurs,5 a concurrent impairment in t-PA release is observed.4,6 Of note, t-PA release and endothelium-dependent vasodilation can predict the risk of cardiovascular events.7,8
Another important stimulus involved in modulating the fibrinolytic system1 is adrenergic activation.9 Because the sympathetic nervous system plays a major role in cardiovascular homeostasis and is involved in the determination of cardiovascular risk,10 the relationship between adrenergic activation and the fibrinolytic system could be relevant in elucidating the pathophysiology of atherothrombosis. Previous human studies have measured circulating t-PA concentrations after systemic stimuli, such as mental stress,11 exercise, or intravenous drug infusions,12,13 which do not necessarily reflect the local amount of t-PA released by endothelial cells.14 This is a crucial issue, because effective fibrinolysis must be sustained by local t-PA release, which cannot be measured by systemic assessment.15,16 The relationship between the adrenergic system and endothelial fibrinolysis is currently not fully characterized, and local t-PA release after adrenergic stimulation represents a major issue requiring further investigation.14
In the present study we hypothesized that the (adrenergic-mediated) t-PA release in response to the adrenergic stimulus is mediated by the NO pathway. Therefore, we have assessed t-PA release in the forearm microcirculation of normotensive subjects and in patients with essential hypertension under specific adrenergic stimuli. In particular, we investigated which adrenergic receptor subtype (ie, 
- or β-adrenoceptor) is involved and the contribution of NO in modulating t-PA release in healthy conditions.
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Materials and Methods |
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Subjects
The study population included 58 healthy male volunteers and 44 patients with essential hypertension. Patients were recruited among newly diagnosed case subjects in our outpatient clinic. Inclusion criteria were age between 30 and 65 years and sitting blood pressure values (after 10 minutes of rest) between 140/90 mm Hg and 160/99 mm Hg, confirmed on 2 separate occasions within a period of 1 month according to European guidelines.17 Exclusion criteria were dyslipidemia, diabetes, smoking, body mass index >30 kg/m2, renal or liver impairment, and established cardiovascular diseases other than essential hypertension. Secondary forms of hypertension were excluded by routine diagnostic procedures. Patients either were never treated for hypertension or they did not receive any medications for
1 month before enrollment in the study. The study protocol was approved by the local ethics committee and performed according to the guidelines of our institution. All of the patients were aware of the nature, purpose, and potential risks of the study and gave their written consent.
Experimental Procedures
The perfused-forearm model used in this study has been described previously in detail.5 Briefly, intravenous catheters were placed into the deep antecubital vein of each arm (experimental and contralateral forearm as control) and the brachial artery of the nondominant arm cannulated for drug infusion at systemically ineffective rates, as well as for the intra-arterial blood pressure and heart rate monitoring. Forearm blood flow (FBF) was measured in both forearms by strain gauge venous plethysmography (EC-6, DE Hokanson, Inc). Before FBF measurement, simultaneous arterial and venous samples for t-PA and plasminogen activator inhibitor (PAI)-1 antigen concentration measurements were collected before and after each infusion of the study drug. Each dose was infused for 15 minutes. Infusions were interrupted during arterial sampling.
Plasma concentrations of t-PA and PAI-1 antigen were determined by ELISA (Tecnoclone GmbH). All of the samples were assayed in duplicate on the same test plate. Intra-assay and interassay coefficients of variation were <10%. Coefficient of variation for FBF repeated measurements in our laboratory is <10%.5
Experimental Design
Relationship Between Adrenergic Stimuli and Acute t-PA and PAI-1 Release in Normotensive Subjects and Essential Hypertensive Patients
t-PA and PAI-1 release in response to intra-arterial administration of 2 doses of epinephrine (0.1 and 0.3 µg/100 mL per minute) were measured in 18 normotensive and 16 essential hypertensive subjects. Intra-arterial ouabain (0.3 and 0.7 µg/100 mL per minute), a vasoconstrictor compound that acts via direct hyperpolarization of vascular smooth cells,18 was used as a control. Epinephrine and ouabain were infused in random order and each dose for a duration of 15 minutes.
NO Contribution to Adrenergic-Mediated t-PA Release in Normotensive Subjects and Essential Hypertensive Patients
To evaluate the contribution of NO to adrenergic-mediated t-PA release, another group of 12 normotensive subjects and 12 hypertensive patients was subjected to infusion of epinephrine (0.1 µg/100 mL per minute) both in the absence and presence of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA; 100 µg/100 mL per minute). Because L-NMMA reduces blood flow, the effect of epinephrine was evaluated in presence of the NO clamp, which allows assessment of endothelial agonists in the presence of NOS blockade without change in basal blood flow, thus avoiding any perturbation that could alter net-forearm t-PA release. Briefly, after 10 minutes of L-NMMA infusion, sodium nitroprusside was coinfused at an adjusted dose (0.3 and 0.4 µg/100 mL per minute) to restore the FBF reduced by L-NMMA infusion to baseline, as described previously in detail.19 Because sodium nitroprusside is an exogenous NO donor acting directly on vascular smooth muscle cells,20 it does not stimulates t-PA release from endothelial cells in vivo.4,21
Receptor Characterization of Adrenergic-Mediated t-PA Release in Normotensive Subjects
To characterize the receptor subtype involved in the adrenergic-induced t-PA release, in another group of 12 normotensive subjects, epinephrine (0.1 µg/100 mL per minute) was infused either in the presence of phentolamine (8 µg/100 mL per minute) or of propanolol (10 µg/100 mL per minute), an - and β-receptor blocker, respectively. Each drug was preinfused for 10 minutes in random order. The effectiveness of these infusion rates was validated in previous studies.22,23
Effect of Selective β-Receptor Stimulation and NO Contribution on t-PA Release in Normotensive Subjects and Essential Hypertensive Patients
To confirm the role of β-receptors in endothelial t-PA release, in another group of 16 normotensive subjects and 16 hypertensive patients, isoproterenol (0.03 µg/100 mL per minute), a β-selective agonist, was infused in the absence and presence of L-NMMA, using the NO clamp technique. Isoproterenol was infused for 15 minutes. To exclude the possible confounding effect of flow increase, a dose-response curve to intra-arterial sodium nitroprusside (0.5 to 1.0 µg/100 mL per minute), a direct smooth muscle cell relaxant, was performed.
Data Analysis
Forearm plasma flow was determined by FBF and hematocrit. Net forearm release or uptake rates for t-PA and PAI-1 were calculated by the following formula: net release=(Cv–Ca)x[FBFx (101–hematocrit)/100], where Cv and Ca are the venous and arterial concentrations, respectively. A positive value indicates a net release, whereas a negative value indicates an uptake of the fibrinolytic component. The total amount of t-PA released was calculated using the area under the curve formula for repeated measures.24 Study population characteristics, basal venous and arterial concentrations, and t-PA balance at baseline were compared using the Student t test or nonparametric test, depending on the results of the test for normality. Responses to epinephrine, isoproterenol, and ouabain were analyzed by 1-way (infusion) and 2-way (group and infusion) ANOVAs for repeated measures, applying the Bonferroni posthoc analysis. Results were expressed as means±SDs. Findings were considered statistically significant at P<0.05. Computations for the power calculation and for the statistical methods were performed using SPSS 15.0 statistics software. The present study was designed to have the 80% power at the 5% level to detect a 30% modification in fibrinolytic component release after drug infusion.
Drugs
Epinephrine (Biologici Italia), isoproterenol (Abbott), L-NMMA (Clinalfa AG), sodium nitroprusside (Malesci SpA), ouabain (Clinalfa AG), propanolol (Astra Zeneca), and phentolamine (Novartis) were obtained from commercially available sources and diluted to the desired concentration by the addition of normal saline. Sodium nitroprusside was dissolved in 5% glucose solution and protected from light by aluminum foil.
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Results |
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Clinical characteristics of the study population are shown in Table. Groups were similar in characteristics except for systolic and diastolic blood pressure values, which were significantly higher in the hypertensive patients. No changes in intra-arterial blood pressure or heart rate were observed during intrabrachial drug infusion (data not shown).
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Adrenergic Stimuli and Acute t-PA and PAI-1 Release in Normotensive Subjects and Essential Hypertensive Patients
Normotensive subjects showed a dose-dependent vasoconstriction in response to epinephrine that was significantly lower than that observed in the hypertensive patients (Figure 1A). In contrast, vasoconstriction to ouabain was similar in the 2 groups (Figure 1B).
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). Effect of epinephrine (C) and ouabain (D) on t-PA release in normotensive subjects (•) and essential hypertensive patients (
P<0.01 vs baseline.At baseline, arterial and venous concentrations of t-PA were significantly (P<0.05) lower in hypertensive patients than in the normotensive subjects (arterial: 0.5±0.1 versus 3.7±0.3 ng/mL; venous: 0.5±0.1 versus 3.8±0.2 ng/mL). In the normotensive group, net t-PA release significantly increased during epinephrine infusion, a maximal effect being observed with the lower dose of the agonist (Figure 1C). By contrast, in hypertensive patients, t-PA release was reduced, reaching a peak effect with the higher dose of epinephrine (Figure 1C). Accordingly, the total amount of t-PA released was significantly lower in hypertensive patients as compared with control subjects (1.2±0.4 versus 4.3±1.7 ng/100 mL of forearm tissue; P<0.01). No significant difference in net t-PA release was recorded in either group after ouabain infusion (Figure 1D). At baseline, arterial and venous concentrations of PAI-1 antigen were similar in normotensive subjects and hypertensive patients (arterial: 29.8±4.8 versus 27.6±5.2 ng/mL; venous: 30.0±5.0 versus 27.7±5.7 ng/mL). No significant difference in net PAI-1 release after epinephrine infusion was noted in either the normotensive subjects (from 0.5±0.2 to 0.7±0.3 ng/min per 100 mL of forearm tissue) or the hypertensive patients (from 0.7±0.3 to 0.6±0.2 ng/min per 100 mL of forearm tissue). Similarly, no significant changes in t-PA release were observed after ouabain infusions in both normotensive (from 0.8±0.3 to 0.9±0.4 ng/min per 100 mL of forearm tissue) and hypertensive (from 0.8±0.3 to 1.0±0.5 ng/min per 100 mL of forearm tissue) groups.
NO Contribution to Adrenergic-Mediated t-PA Release in Normotensive Subjects and Essential Hypertensive Patients
In normotensive subjects, a lower vasoconstriction to intrabrachial epinephrine as compared with hypertensive patients was observed (Figure 2A and 2B). Vasoconstriction in response to epinephrine in normotensive subjects was increased by the NOS blockade with L-NMMA, which significantly reduced basal FBF (Figure 2A). In hypertensive patients, L-NMMA infusion, which reduced basal FBF insignificantly, did not modify epinephrine-induced vasoconstriction (Figure 2B).
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) and after (
) epinephrine infusion during saline or L-NMMA in normotensive subjects (C) and hypertensive patients (D). *P<0.05 vs saline infusion; In normotensive subjects, the lower dose of epinephrine induced a significant increase in t-PA release (Figure 2C). Moreover, the NOS blockade with L-NMMA decreased basal t-PA release (from 0.2±0.1 to –0.1±0.0 ng/min per 100 mL of forearm tissue; P<0.05) and significantly blunted epinephrine-induced t-PA release (Figure 2C). In contrast, epinephrine-induced t-PA release in hypertensive patients was significantly lower as compared with normotensive subjects (P<0.01), and L-NMMA coinfusion failed to affect either constitutive (from 0.1±0.0 to 0.1±0.1 ng/min per 100 mL of forearm tissue) or stimulated t-PA release (Figure 2D).
Receptor Characterization of Adrenergic-Mediated t-PA Release in Normotensive Subjects
In the group of normotensive subjects, a nonsignificant vasoconstriction in response to the lower dose of epinephrine was observed (Figure 3A). Phentolamine preinfusion significantly increased FBF (Figure 3A). In the presence of -blockade by phentolamine, epinephrine induced a significant vasodilation (Figure 3A). By contrast, in the presence of β-blockade with propanolol, which failed to significantly affect FBF when preinfused, epinephrine induced a significant vasoconstrictor effect (Figure 3B).
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Intrabrachial infusion of the lower dose of epinephrine significantly increased net t-PA release, a response not affected by phentolamine coinfusion (Figure 3C). In contrast, epinephrine-induced t-PA release was abolished in the presence of propanolol (Figure 3D).
Effect of Selective β-Receptor Stimulation and NO Contribution on t-PA Release in Normotensive Subjects and Essential Hypertensive Patients
Normotensive subjects exhibited vasodilation to isoproterenol similar to that observed in hypertensive patients (Figure 4A and 4B). In healthy subjects, vasodilation to isoproterenol was significantly reduced by L-NMMA infusion (Figure 4A), whereas in hypertensive patients L-NMMA infusion only caused nonsignificant reduction in vasodilation to isoproterenol (Figure 4B). Vascular response to sodium nitroprusside was found to be similar in the 2 groups (normotensive subjects: FBF from 3.5±0.2 to 18.2±0.9 mL/min per 100 mL of forearm tissue; hypertensive patients: FBF from 3.5±0.3 to 18.4±0.6 mL/min per 100 mL of forearm tissue; P value not significant).
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In normotensive subjects, isoproterenol induced a significant increase in net t-PA release versus baseline (Figure 4C). L-NMMA infusion, which reduced constitutive t-PA release (from 0.2±0.1 to –0.2±0.0 ng/min per 100 mL of forearm tissue; P<0.05), significantly blunted isoproterenol-induced t-PA release (Figure 4C). By contrast, in hypertensive patients, isoproterenol-induced t-PA release was significantly reduced as compared with normotensive subjects, and L-NMMA infusion failed to significantly affect both constitutive (0.2±0.0 to 0.1±0.0 ng/min per 100 mL of forearm tissue) and stimulated t-PA release (Figure 4D). No significant increase in t-PA release was observed during sodium nitroprusside infusion (from 0.2±0.1 to 0.3±0.1 ng/min per 100 mL of forearm tissue). In both groups, contralateral FBF and venous-arterial concentrations of t-PA remained unchanged throughout each protocol (data not shown).
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Discussion |
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The main finding of the present study is that, in physiological conditions, adrenergic stimulation induces t-PA release via the activation of β-adrenergic–mediated NO pathway. Contrastingly, in hypertensive patients, β-adrenergic activation of the t-PA/NO pathway is impaired, an alteration potentially involved in the hypofibrinolytic state characterizing this clinical condition.4,6
In normotensive subjects, epinephrine infusion caused a dose-dependent vasoconstriction and a net release of t-PA but not of its inhibitor PAI-1. In the same experimental conditions, the infusion of ouabain, despite inducing a similar vasoconstriction, failed to increase the release of t-PA and PAI-1. Taken together, these results indicate that epinephrine- and possibly adrenergic-mediated t-PA release in healthy subjects is a specific and flow-independent endothelial property.
In normotensive subjects, vasoconstriction to epinephrine was significantly lower as compared with hypertensive patients, in line with the previous findings of an imbalance of adrenoreceptors in essential hypertension.25,26 Although epinephrine is a potent nonselective adrenergic agonist with a higher affinity for β-adrenoreceptors, it induces vasoconstriction when infused locally.27 This effect, related to the higher density of -receptors in peripheral arterioles,27 is part of the hemostatic effect of epinephrine, which is also mediated via platelet aggregation and the increase of several clotting factors.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-1.6,28
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.4,30
The NO pathway also plays a crucial role in modulating the vascular effects of epinephrine in healthy conditions. In normotensive subjects, L-NMMA, an NOS inhibitor, decreased basal flow and accentuated the vasoconstriction in response to epinephrine. The latter effect is probably related to the NO activation induced by the β-adrenoceptor component of the epinephrine response.31
By contrast, no significant modification in either tonic or epinephrine-induced t-PA release was observed during L-NMMA coinfusion in hypertensive patients. Moreover, in hypertensive patients, basal vasoconstriction to L-NMMA was reduced, and the inhibition of NOS did not have any effect on the vascular response to epinephrine. Taken together, these findings confirm the presence of impaired NO availability in essential hypertension,18,32–34 which accounts for the reduced endothelial t-PA release capacity in this clinical condition, as already documented with different stimuli.4,6
To elucidate the receptor subtype involved in the modulation of fibrinolysis by adrenergic stimuli, we assessed the effect of epinephrine on t-PA release in the presence of either phentolamine, an -antagonist, or propanolol, a β-antagonist, in a group of normotensive subjects. The results show that -blockade, which induced significant vasodilation to epinephrine, failed to affect t-PA release.
In contrast, the blockade of β-adrenoceptors with propanolol, which potentiated vasoconstriction to epinephrine, significantly blunted t-PA release after epinephrine infusion. These findings support the possibility that epinephrine-induced t-PA release across the forearm microcirculation is mediated by β-adrenoreceptors.21 A final demonstration is provided by the study with the selective β-adrenergic agonist isoproterenol. In normotensive subjects isoproterenol caused vasodilation and a parallel t-PA release. Note that both effects were blunted by L-NMMA. In hypertensive patients, whereas vasodilation to isoproterenol was similar to that of controls, but unaffected by L-NMMA coinfusion, β-adrenoceptor–induced t-PA release was still present but significantly reduced.
The results of the present study are in contrast with those of a previous study in which a lacking effect of NOS inhibition on bradykinin-induced t-PA release was reported.35 Indeed, in this study, L-NMMA infusion failed to significantly affect vasodilation to bradykinin in healthy subjects. Therefore, an incomplete endothelial NOS inhibition, which may account for the lacking effect on t-PA release, cannot be excluded.
The discrepancy between the vascular and fibrinolytic effects of isoproterenol observed in hypertensive patients requires further explanation. It is conceivable that, whereas mechanisms compensating for the reduced NO availability, eg, hyperpolarization,36 may account for the similar degree of vasodilation, a preserved NO pathway is crucial to maintain adequate t-PA release. Recent experimental findings support the hypothesis that the reduced, but still present, t-PA release observed in our hypertensive patients might be sustained by a noncompensatory endothelial-derived hyperpolarizing factor–dependent pathway.37 Muldowney et al37 reported that the endothelial-derived hyperpolarizing factor 5,6-epoxyeicosatrienoic acid induces the exocytosis of t-PA from storage granules via calcium- and cAMP-dependent pathways, in line with previous experimental findings.38,39 According to our findings, 5,6-epoxyeicosatrienoic acid–mediated t-PA release was not affected by the ouabain-dependent part of the endothelial-derived hyperpolarizing factor pathway.37
The major limitation of the present in vivo clinical study concerns the assessment of dynamic endothelial t-PA release in the forearm. Indeed, although this vascular district is less susceptible to atherothrombosis, it is less invasive and is considered a valid surrogate of the coronary circulation.1 Moreover, the dynamic assessment of t-PA release across the entire vascular forearm bed does not necessarily reflect the local capacity for t-PA release at the site of developing thrombus.
In the present study we did not measure t-PA and PAI-1 activity or fibrin degradation products to estimate the activity of the fibrinolytic system. However, several findings14,40 indicate that, in the presence of no demonstrable release of PAI-1 antigen across the forearm, as in our experimental conditions, t-PA antigen concentration increases in parallel with t-PA activity.1
Perspectives
The results of the present study demonstrate that adrenergic-induced t-PA release is mediated by β-adrenoreceptors via a mechanism that involves the NO pathway. In essential hypertension, the reduced NO availability impairs adrenergic-mediated t-PA release, possibly playing a crucial role in determining the hypofibrinolytic state characterizing this clinical condition. The reduced dynamic endothelial t-PA release could be part of a generalized endothelial dysfunction that characterizes essential hypertensive patients and contributes to the risk of atherothrombotic events.7,41 Thus, understanding the mechanisms underlying stimulated t-PA release could lead to specific therapeutic strategies to improve endothelial fibrinolytic function and possibly reduce cardiovascular risk in essential hypertension.
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Acknowledgments |
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We gratefully acknowledge Dr M. Urooj Zafar for his help in the revision of the article.
Disclosures
None.
Received February 11, 2008; first decision February 25, 2008; accepted May 29, 2008.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Oliver JJ, Webb DJ, Newby DE. Stimulated tissue plasminogen activator release as a marker of endothelial function in humans. Arterioscler Thromb Vasc Biol. 2005; 25: 2470–2479.
2. Emeis JJ. Regulation of the acute release of tissue-type plasminogen activator from the endothelium by coagulation activation products. Ann N Y Acad Sci. 1992; 667: 249–258.[Medline] [Order article via Infotrieve]
3. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ. Endothelial function and dysfunction. Part I: methodologic issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005; 23: 7–17.[CrossRef][Medline] [Order article via Infotrieve]
4. Giannarelli C, De Negri F, Virdis A, Ghiadoni L, Cipriano A, Magagna A, Taddei S, Salvetti A. Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients. Hypertension. 2007; 49: 878–884.
5. Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation. 1998; 97: 2222–2229.
6. Hrafnkelsdottir T, Wall U, Jern C, Jern S. Impaired capacity for endogenous fibrinolysis in essential hypertension. Lancet. 1998; 352: 1597–1598.[CrossRef][Medline] [Order article via Infotrieve]
7. Robinson SD, Ludlam CA, Boon NA, Newby DE. Endothelial fibrinolytic capacity predicts future adverse cardiovascular events in patients with coronary heart disease. Arterioscler Thromb Vasc Biol. 2007; 27: 1651–1656.
8. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005; 111: 363–368.
9. von Kanel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol. 2000; 65: 357–369.[CrossRef][Medline] [Order article via Infotrieve]
10. Mancia G, Grassi G, Giannattasio C, Seravalle G. Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension. 1999; 34: 724–728.
11. Jern C, Selin L, Jern S. In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. Thromb Haemost. 1994; 72: 285–291.[Medline] [Order article via Infotrieve]
12. Chandler WL, Levy WC, Stratton JR. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Circulation. 1995; 92: 2984–2994.
13. Chandler WL, Levy WC, Veith RC, Stratton JR. A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training. Blood. 1993; 81: 3293–3302.
14. Hrafnkelsdottir T, Gudnason T, Wall U, Jern C, Jern S. Regulation of local availability of active tissue-type plasminogen activator in vivo in man. J Thromb Haemost. 2004; 2: 1960–1968.[CrossRef][Medline] [Order article via Infotrieve]
15. van Zonneveld AJ, Veerman H, Pannekoek H. On the interaction of the finger and the kringle-2 domain of tissue-type plasminogen activator with fibrin. Inhibition of kringle-2 binding to fibrin by epsilon-amino caproic acid. J Biol Chem. 1986; 261: 14214–14218.
16. Ranby M. Studies on the kinetics of plasminogen activation by tissue plasminogen activator. Biochim Biophys Acta. 1982; 704: 461–469.[CrossRef][Medline] [Order article via Infotrieve]
17. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003; 21: 1011–1053.[CrossRef][Medline] [Order article via Infotrieve]
18. Taddei S, Ghiadoni L, Virdis A, Buralli S, Salvetti A. Vasodilation to bradykinin is mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertensive patients. Circulation. 1999; 100: 1400–1405.
19. Virdis A, Ghiadoni L, Cardinal H, Favilla S, Duranti P, Birindelli R, Magagna A, Bernini G, Salvetti G, Taddei S, Salvetti A. Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension. J Am Coll Cardiol. 2001; 38: 1106–1115.
20. Schultz K, Schultz K, Schultz G. Sodium nitroprusside and other smooth muscle-relaxants increase cyclic GMP levels in rat ductus deferens. Nature. 1977; 265: 750–751.[CrossRef][Medline] [Order article via Infotrieve]
21. Stein CM, Brown N, Vaughan DE, Lang CC, Wood AJ. Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature. J Am Coll Cardiol. 1998; 32: 117–122.
22. Taddei S, Salvetti A, Pedrinelli R. Persistence of sympathetic-mediated forearm vasoconstriction after alpha-blockade in hypertensive patients. Circulation. 1989; 80: 485–490.
23. Taddei S, Salvetti A, Pedrinelli R. Ouabain vasoconstricts human forearm arterioles through alpha-adrenergic stimulation. J Hypertens. 1988; 6 (suppl): S357–S359.
24. Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology. 2003; 28: 916–931.[CrossRef][Medline] [Order article via Infotrieve]
25. Iaccarino G, Cipolletta E, Fiorillo A, Annecchiarico M, Ciccarelli M, Cimini V, Koch WJ, Trimarco B. Beta(2)-adrenergic receptor gene delivery to the endothelium corrects impaired adrenergic vasorelaxation in hypertension. Circulation. 2002; 106: 349–355.
26. Gros R, Chorazyczewski J, Meek MD, Benovic JL, Ferguson SS, Feldman RD. G-protein-coupled receptor kinase activity in hypertension: increased vascular and lymphocyte G-protein receptor kinase-2 protein expression. Hypertension. 2000; 35: 38–42.
27. Guimaraes S, Moura D. Vascular adrenoceptors: an update. Pharmacol Rev. 2001; 53: 319–356.
28. Ridderstrale W, Ulfhammer E, Jern S, Hrafnkelsdottir T. Impaired capacity for stimulated fibrinolysis in primary hypertension is restored by antihypertensive therapy. Hypertension. 2006; 47: 686–691.
29. Fox KA, Robison AK, Knabb RM, Rosamond TL, Sobel BE, Bergmann SR. Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator. Circulation. 1985; 72: 1346–1354.
30. Newby DE, Wright RA, Dawson P, Ludlam CA, Boon NA, Fox KA, Webb DJ. The L-arginine/nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man. Cardiovasc Res. 1998; 38: 485–492.
31. Schlaich MP, Ahlers BA, Parnell MM, Kaye DM. Beta-Adrenoceptor-mediated, nitric-oxide-dependent vasodilatation is abnormal in early hypertension: restoration by L-arginine. J Hypertens. 2004; 22: 1917–1925.[CrossRef][Medline] [Order article via Infotrieve]
32. Cardillo C, Kilcoyne CM, Quyyumi AA, Cannon RO III, Panza JA. Selective defect in nitric oxide synthesis may explain the impaired endothelium-dependent vasodilation in patients with essential hypertension. Circulation. 1998; 97: 851–856.
33. Garovic VD, Joyner MJ, Dietz NM, Boerwinkle E, Turner ST. Beta(2)-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans. J Physiol. 2003; 546: 583–589.
34. Ferro A, Coash M, Yamamoto T, Rob J, Ji Y, Queen L. Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt. Br J Pharmacol. 2004; 143: 397–403.[CrossRef][Medline] [Order article via Infotrieve]
35. Brown NJ, Gainer JV, Murphey LJ, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Circulation. 2000; 102: 2190–2196.
36. Taddei S, Versari D, Cipriano A, Ghiadoni L, Galetta F, Franzoni F, Magagna A, Virdis A, Salvetti A. Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients. J Am Coll Cardiol. 2006; 48: 508–515.
37. Muldowney JA III, Painter CA, Sanders-Bush E, Brown NJ, Vaughan DE. Acute tissue-type plasminogen activator release in human microvascular endothelial cells: the roles of Galphaq, PLC-beta, IP3 and 5,6-epoxyeicosatrienoic acid. Thromb Haemost. 2007; 97: 263–271.[Medline] [Order article via Infotrieve]
38. Tranquille N, Emeis JJ. On the role of calcium in the acute release of tissue-type plasminogen activator and von Willebrand factor from the rat perfused hindleg region. Thromb Haemost. 1991; 66: 479–483.[Medline] [Order article via Infotrieve]
39. Hegeman RJ, van den Eijnden-Schrauwen Y, Emeis JJ. Adenosine 3':5'-cyclic monophosphate induces regulated secretion of tissue-type plasminogen activator and von Willebrand factor from cultured human endothelial cells. Thromb Haemost. 1998; 79: 853–858.[Medline] [Order article via Infotrieve]
40. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost. 1997; 77: 522–525.[Medline] [Order article via Infotrieve]
41. Poli KA, Tofler GH, Larson MG, Evans JC, Sutherland PA, Lipinska I, Mittleman MA, Muller JE, D'Agostino RB, Wilson PW, Levy D. Association of blood pressure with fibrinolytic potential in the Framingham offspring population. Circulation. 2000; 101: 264–269.
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