tPA Activity Research Articles

Role of tissue plasminogen activator in the sensitization of methamphetamine‐induced dopamine release in the nucleus accumbens

We have previously demonstrated that repeated, but not acute, methamphetamine (METH) treatment increases tissue plasminogen activator (tPA) activity in the brain, which is associated with the development of behavioral sensitization to METH. In this study, we investigated whether the tPA-plasmin system is involved in the development of sensitization in METH-induced dopamine release in the nucleus accumbens (NAc). There was no difference in acute METH-induced increase in extracellular dopamine levels in the NAc between wild-type and tPA-deficient (tPA-/-) mice. Repeated METH treatment resulted in a significant enhancement of METH- induced dopamine release in wild-type mice, but not tPA-/- mice. Microinjection of exogenous tPA or plasmin into the NAc of wild-type mice significantly potentiated acute METH- induced dopamine release. Degradation of laminin was evident in brain tissues incubated with tPA plus plasminogen or plasmin in vitro although tPA or plasminogen alone had no effect. Immunohistochemical analysis revealed that microinjection of plasmin into the NAc reduced laminin immunoreactivity without neuronal damage. Our findings suggest that the tPA-plasmin system participates in the development of behavioral sensitization induced by repeated METH treatment, by regulating the processes underlying the sensitization of METH-induced dopamine release in the NAc, in which degradation of laminin by plasmin may play a role.

Adaptation of Coagulation and Fibrinolysis in Allogeneic Stem Cell Transplantation.

Allogeneic stem cell transplantation (SCT) seems to result in activation of coagulation and fibrinolysis. We characterised the outcome of SCT and graft versus host disease (GvHD) in association with the adaptive mechanisms of coagulation and fibrinolysis. 30 patients given myeloablative conditioning with cyclophosphamide and total body irradiation underwent allogeneic SCT for a hematological malignancy. 19 patients received the transplant from a sibling and 11 from an unrelated donor. GvHD prophylaxis consisted of cyclosporine and methotrexate, and in addition methylprednisolone in case of a sibling donor. Eight patients developed GvHD during the 3-month follow-up. Several coagulation and fibrinolysis activities were serially assessed: antithrombin, protein C (PC), FVIII, prothrombin fragments 1+2 (F1+2), D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1). During the conditioning therapy as an early sign of thrombin generation, F1+2 increased 3-fold and D-dimer 4-fold, compatible with enhanced fibrin turnover. The activity of tPA reached its maximum already before the engraftment and that of PAI-1 diminished accordingly. FVIII increased steadily from normal to reach maximum (up to 273% ±104%, median ±SD, p<0.001) after engraftment. Interestingly, the natural anticoagulant, PC rose (up to 189% ± 63%) in parallel with FVIII, but showed a 5-fold individual variability. After the engraftment the FVIII, PC and antihrombin levels were highly interrelated. Clinically relevant prognostic association was observed between early low PC activity and the appearance of GvHD: the level of PC lower than 90% during the conditioning therapy was associated and even predicted (p=0.007) acute GvHD (OR=16.7). After the transplantation the level of F1+2 over 2.5 nmol/l associated and predicted the non-relapse mortality (p=0.024). Three patients with the largest early thrombin generation all died during a longer follow-up (6–24 months). Also, elevated PAI-1 activity (>10 U/ml) predicted the non-relapse mortality (p=0.013). In conclusion, early activation of coagulation and fibrinolysis is followed by increased FVIII and PC activities in SCT. Early marked thrombin generation and elevated PAI-1 associated with the non-relapse mortality and low PC activity with the appearance of acute GvHD.

Two photon absorption of extended substituted phenylenevinylene oligomers: A TDDFT study

Time dependent density functional theory has been applied to analyze the effect of substituent groups on one-photon (OPA) and two-photon (TPA) absorption properties of extended amine-terminated phenylenevinylene oligomers. All investigated molecules are characterized by increased TPA activity. Calculated TPA cross-sections for these compounds do not show TPA enhancements observed in experimental measurements. Stabilization of the TPA active excited state in these chromophores leads to the small (∼0.2 eV) energy separation between the OPA and TPA allowed excited states, which agrees well with experimental data and may lead to the enhancement of the TPA response due to the strong vibronic couplings.

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

During neuroinflammation in multiple sclerosis (MS) fibrinogen, not normally present in the brain or spinal cord, enters the central nervous system through a compromised blood-brain barrier. Fibrin deposited on axons is ineffectively removed by tissue plasminogen activator (tPA), a key contributory factor being the upregulation of plasminogen activator inhibitor-1 (PAI-1). This study investigated the role of PAI-1 during experimental neuroinflammatory disease. Chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of MS, was induced with spinal cord homogenate in PAI-1 knockout (PAI-1(-/-)) and wild type (WT) mice, backcrossed onto the Biozzi background. Disease incidence and clinical severity were reduced in PAI-1(-/-) mice, with animals developing clinical signs significantly later than WTs. Clinical relapses were absent in PAI-1(-/-) mice and the subsequent reduction in neuroinflammation was coupled with a higher capacity for fibrinolysis in spinal cord samples from PAI-1(-/-) mice, in association with increased tPA activity. Axonal damage was less apparent in PAI-1(-/-) mice than in WTs, implicating fibrin in both inflammatory and degenerative events during CREAE. PAI-1 is a potential target for therapy in neuroinflammatory degenerative diseases, allowing effective fibrin removal and potentially reducing relapse rate and axonal damage.

Development of a new test for the global fibrinolytic capacity in whole blood.

The development of global tests for the fibrinolytic capacity in blood is hampered by the low base-line fibrinolytic activity in blood, by the involvement of both plasmatic components and blood cells in the fibrinolytic system and by the loss of fibrinolytic activity as a result of the action of plasminogen activator inhibitor-1 (PAI-1). To develop a new test for the global fibrinolytic capacity (GFC) of whole blood samples. Collection of blood in thrombin increased the subsequent generation of fibrin degradation products. This was ascribed to rapid clot formation and concomitant reduction of in vitro neutralization of tissue-type plasminogen activator (tPA) by PAI-1. On the basis of this observation, the following test was designed: blood samples were collected in thrombin with and without aprotinin and clots were incubated for 3 h at 37 degrees C. The GFC was assessed from the difference between the fibrin degradation products in the two sera. The assay was applied to blood samples from patients and healthy subjects. Other hemostasis parameters were determined in plasma samples taken simultaneously. The GFC varied considerably (normal range 0.13-13.6 microg mL(-1)); physical exercise strongly increased the GFC. Statistically significant correlations were found with tPA activity, PAI-1 activity and fibrinogen level. A mixture of antibodies against tPA and urokinase-type plasminogen activator (uPA) completely inhibited the GFC. An inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFI) accelerated fibrinolysis 8-fold. The new test represents a global assessment of the main fibrinolytic factors in plasma and potentially those associated with blood cells.

Heating of carbon dioxide during insufflation alters the peritoneal fibrinolytic response to laparoscopic surgery

Laparoscopic surgery is evolving rapidly. It involves the creation of a pneumoperitoneum, mostly using carbon dioxide. Cooling of the peritoneum, due to insufflation, might traumatize the peritoneum and disturb peritoneal fibrinolysis, important in peritoneal healing processes. The current study was performed to elucidate the effects of the temperature of insufflation gas on the peritoneal fibrinolytic response to laparoscopic surgery. Thirty patients scheduled for laparoscopic cholecystectomy were randomized in two groups: one group in which the pneumoperitoneum was created with carbon dioxide at room temperature, and one wherein carbon dioxide at body temperature was used. Peritoneal biopsies were taken at the start and at the end of surgery. Tissue concentrations of tPA antigen, tPA activity, uPA antigen, and PAI-1 antigen were measured using ELISA techniques. Peritoneal PAI-1 antigen levels were significantly higher at the end of the procedure in patients operated with carbon dioxide at room temperature (p < .05). A slight, but not significant, decrease in tPA antigen and activity was observed in both groups during the procedure. Peritoneal concentrations of uPa antigen did not change during the procedure. The temperature of carbon dioxide used for insufflation of the abdominal cavity affects peritoneal biology. Cooling of the peritoneum by unheated carbon dioxide causes increased peritoneal PAI-1 levels, important in peritoneal healing processes.

Testosterone upregulation of tissue type plasminogen activator expression in Sertoli cells

Our previous studies have demonstrated that tissue type plasminogen activator (tPA) might be involved in matrix degradation of blood-testis barrier in rat. In this study, we have further investigated the effect of testosterone (T) on tPA production in rat Sertoli cells. Our results showed that Sertoli cells isolated from rat testes at various ages in vitro secreted tPA in an age-dependent manner. The tPA activity was detected on day 20 after birth, and reached maximum on day 60. The Sertoli cells isolated from the testes on day 20 were then cultured in the presence or absence of testosterone, FSH, and forskolin, the tPA activities were upregulated by T, FSH and forskolin. Addition of H89 or U0126, both inhibited the testosterone-, FSH-, and forskolin-induced tPA expression. It is suggested that FSH- and testosterone-stimulated tPA expression in Sertoli cells may be via PKA and ERK signal transduction. Furthermore, we have observed that testosterone stimulated tPA secretion at all the stages of spermatogenesis (II-VI, VII-VIII, IX-XII and XIII-I), the highest stimulation of tPA activity was observed at stages VII-VIII. This study further suggests that testosterone-induced tPA activity in the Sertoli cells might be related to the function of blood-testis barrier opening and/or closing.

An Evaluation of Normal Saline and Taurolidine on Intra-Abdominal Adhesion Formation and Peritoneal Fibrinolysis

Intraoperative lavage with normal saline or taurolidine solutions is commonly used in abdominal surgery. For this purpose, normal saline and taurolidine, which may modify the intrinsic fibrinolytic activity of the peritoneum by breaking the peritoneal adhesions, are frequently used. We aimed to evaluate how normal saline and taurolidine affect peritoneal fibrinolysis and adhesion formation. A rat model of peritoneal adhesion was used. Control animals received no medication, while normal saline or taurolidine solutions were administered intraperitoneally to the remaining two groups (n = 20 for each group). At postoperative day 10 adhesions were graded, and cardinal parameters of peritoneal fibrinolysis (activities and concentrations of tissue plasminogen activator [tPA], plasminogen activator inhibitor type 1 [PAI-1], and tPA/PAI-1 complex), and hydroxyproline contents were determined in peritoneal tissue samples. Total adhesion scores were decreased in both of the treated groups. Median tissue levels of tPA and tPA activity were higher in the treated groups versus controls. The PAI-1 levels were similar among the three groups. tPA/PAI-1 complex levels were higher in animals that received normal saline and in those treated with taurolidine solution compared with control animals. Peritoneal hydroxyproline levels were similar across the three groups. Our results suggest that normal saline and taurolidine solution administrations might reduce peritoneal adhesion formation, probably by altering peritoneal fibrinolytic activity.

Tissue-Type Plasminogen Activator and the Low-Density Lipoprotein Receptor-Related Protein Mediate Cerebral Ischemia-Induced Nuclear Factor-κB Pathway Activation

Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space and the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is a member of the low-density lipoprotein receptor gene family found in neurons and astrocytes. Cerebral ischemia induces activation of the nuclear factor (NF)-kappaB pathway. The present study investigated the role that the interaction between tPA and LRP plays on middle cerebral artery occlusion (MCAO)-induced NF-kappaB-mediated inflammatory response. We found that MCAO increased LRP expression primarily in astrocytes and that this effect was significantly decreased in the absence of tPA. The onset of the ischemic insult induced activation of the NF-kappaB pathway in wild-type and plasminogen (Plg(-/-))-deficient mice, and this effect was attenuated after inhibition of LRP or genetic deficiency of tPA. Moreover, administration of tPA to tPA(-/-) mice resulted in activation of the NF-kappaB pathway comparable with that observed in wild-type and Plg(-/-) mice. We also report that inhibition of either tPA activity or LRP or genetic deficiency of tPA resulted in a significant decrease in MCAO-induced nitric oxide production and inducible nitric-oxide synthase expression. In conclusion, our results demonstrate that after MCAO the interaction between tPA and LRP results in NF-kappaB activation in astrocytes and induction of inducible nitric-oxide synthase expression in the ischemic tissue, suggesting a cytokine-like plasminogen-independent role for tPA during cerebral ischemia.

Activation of post‐synaptic dopamine D1 receptors promotes the release of tissue plasminogen activator in the nucleus accumbens via PKA signaling

We have previously demonstrated that tissue plasminogen activator (tPA) plays an important role through the conversion of plasminogen to plasmin in the release of dopamine in the nucleus accumbens (NAc) evoked by depolarization or the systemic administration of drugs of abuse such as morphine and nicotine. In the present study, we examined the mechanisms by which drugs of abuse increase extracellular tPA activity in the NAc in vivo using in situ zymography. The dopamine D(1) receptor (D(1) R) agonist SKF38393, but not D(2) receptor agonist quinpirole, significantly increased extracellular tPA activity in the NAc. The effect of SKF38393 was blocked by pre-treatment with the dopamine D(1) R antagonist SCH23390. Microinjection of Rp-cAMPs, a protein kinase A inhibitor, into the NAc completely blocked the effect of SKF38393. Systemic administration of morphine and methamphetamine increased extracellular tPA activity in the NAc, and these effects were completely blocked by pre-treatment with SCH23390 and raclopride. The results suggest that activation of post-synaptic dopamine D(1) Rs in the NAc leads to an increase in extracellular tPA activity via protein kinase A signaling. Furthermore, dopamine D(2) receptors are also involved in the release of tPA induced by morphine and methamphetamine.

Fibrinolytic responses of human peritoneal fluid in laparoscopic cholecystectomy: a prospective clinical study

The reduction in peritoneal fibrinolysis is believed to be the pathogenetic mechanism of adhesion formation. The general conclusion based on previous clinical and experimental studies is that laparoscopic procedures produce less adhesion formation. The association between this beneficial effect of laparoscopic cholecystectomy and peritoneal fibrinolytic changes is not clear. Therefore, the authors aimed to compare the effects of open and laparoscopic cholecystectomy on peritoneal fibrinolysis. For this purpose, fibrinolytic parameters in peritoneal fluid were investigated 24 h after laparoscopic and open cholecystectomies. In a prospective clinical study, peritoneal fluid was sampled via a drain 24 h after laparoscopic (n = 10) and open (n = 9) cholecystectomies. Activities and concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), and tPA/PAI-1 complex were determined by enzyme-linked immunosorbent assay (ELISA) kits. In peritoneal fluids, tPA and tPA/PAI-1 complex concentrations were higher in the open cholecystectomy group (p = 0.009 and p < 0.001, respectively), but tPA activity and PAI-1 concentrations did not differ between the groups (p = 0.514 and p = 0.716, respectively). Fibrinolytic changes in peritoneal fluid have several similarities in open and laparoscopic cholecystectomies with regard to tPA activity and PAI-1 levels. However, higher tPA levels after the open procedure probably are secondary to more intense tissue handling leading to mesothelial release of tPA.

248: Prognostic Value of Plasminogen Activator Inhibitor-1 and Tissue Plasminogen Activator in the Evaluation of Patients With Chest Pain

Numerous studies have demonstrated that disturbances of the balance between coagulation and fibrinolysis affect the incidence of atherosclerosis-related clinical events. The most important markers of fibrinolytic activity are the levels of PAI-1 and tPA. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of the plasminogen activators tPA and urokinase in the regulation of fibrinolytic balance. Disorders associated with increased thrombosis, such as coronary heart disease, are associated with increased PAI-1 antigen and activity and, in the case of coronary heart disease, decreased tPA activity.

Retroviral gene transfer of tissue-type plasminogen activator targets thrombolysis in vitro and in vivo

Patients usually have serious complications of thrombosis and bleeding by eating anticoagulation medicine for their residual lives after mechanical valve replacement operation. Tissue-type plasminogen activator (tPA) could target thrombolysis by activating plasminogen to fibrinolysin. In this study, we recombined a retroviral vector pLEGFP-N1-tPA and cultured purified packaging cells PT67/pLEGFP-N1-tPA to produce high-titer retrovirus. In vitro, two target cells, endothelial cell of umbilical vein (ECUV) 304 and heart muscle cell (HMC) that consist of endocardium and heart muscle, were infected by pLEGFP-N1-tPA. The results demonstrated that exogenous tPA was successfully transferred into ECUV304 and HMC. tPA in the two cells shows significant thrombolysis in plasma plate and the activity and content of tPA were high. Furthermore, in vivo, no thrombus was seen on the surface of Dacron patches (the same material making up a ring of mechanical valve) by tPA locally transferring around Dacron patches that were transplanted in the inferior caval veins of rabbits. tPA was successfully transferred into the local inferior caval vein. Activity and content of tPA were high in local tissue and blood and thrombolysis was effectively demonstrated by tPA rapidly, efficiently and long expressing. This laid the foundation for study and appliance of the tPA gene valve.

The influence of acute-phase levels of haemostatic factors on reperfusion and mortality in patients with acute myocardial infarction treated with streptokinase

The fibrinolytic system and von Willebrand factor (vWF) have been shown to play a role as risk factors for myocardial infarction. We performed this prospective cohort study to determine if components in the fibrinolytic system or vWF before or during treatment of AMI with streptokinase (SK) could predict reperfusion, recurrent ischaemia, reinfarction or mortality at one year, or mortality at five years. Reperfusion and recurrent ischaemia were assessed by continuous vectorcardiography. The setting was Umeå university hospital and Skellefteå county hospital, Sweden. 139 patients were included; successful reperfusion was obtained in 53%. tPA activity, PAI-activity, PAI-mass concentration and vWF were analysed immediately on arrival and after 4 and 10 h. High fibrinolytic activity, measured as tPA activity > 25 U/L after the start of treatment, was associated with reperfusion. No significant associations between pre-treatment levels of the fibrinolytic variables or vWF and reperfusion or recurrent ischaemia were found. Elevated levels of PAI-1 mass concentration and PAI-1 activity after the start of SK treatment were associated with a higher risk for death at one year, but not at five years. High levels of vWF were associated with worse prognosis but not when corrected for age. Pre-treatment levels of PAI-1, vWF and tPA activity showed no association with reperfusion or recurrent ischaemia. Elevated levels of PAI-1 activity after the start of treatment were associated with worse prognosis.

Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system

Contextual fear conditioning is regulated by the hippocampus, and NR2B, a subunit of the NMDA receptor (NR), is involved in this process. We show that acute stress modulates tissue plasminogen activator (tPA) activity in the hippocampus by inducing expression of its inhibitor, plasminogen activator inhibitor-1. Acute stress increases NR2B expression and ERK1/2 phosphorylation, a classical marker of postsynaptic plasticity, in the hippocampus. tPA forms a complex with NR2B and is necessary for binding NR2B to postsynaptic density-95, allowing for NR activation and membrane anchoring. Acute stress increases the interaction between NR2B and RACK-1, which is also dependent on tPA, further suggesting that tPA is an important factor in NMDA signaling and plasticity in the hippocampus. Finally, acutely stressed tPA(-/-) mice show a decrease in contextual fear conditioning compared with stressed WT mice. These results indicate that tPA is a key modulator in stabilizing the NR complex during stress and participates in changes in behavior and synaptic plasticity.

Novel distribution pattern of fibrinolytic components in rabbit tissues extract: a preliminary study

The purpose of this work was to investigate the distribution pattern of fibrinolytic factors and their inhibitors in rabbit tissues. The components of the fibrinolytic system in extracts from a variety of rabbit tissues, including tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), plasminogen (Plg), plasmin (Pl) and alpha(2) plasmin inhibitor (alpha(2)PI), were determined by colorimetric assay. The tissue extracts in renal, small intestine, lung, brain and spleen demonstrated strong fibrinolytic function, in which high activity of tPA, Plg and Pl was manifested; whereas in skeletal muscle, tongue and stomach, higher activity of PAI-1 and alpha(2)PI showed obviously. Also excellent linear correlations were found between levels of tPA and PAI-1, Pl and alpha(2)PI, Plg and Pl. In related tissues, renal cortex and renal marrow showed distinctly higher activity of tPA and lower activity of PAI-1, with the levels of Plg and Pl in renal cortex being higher than those in renal marrow, where the alpha(2)PI level was higher than that in renal cortex. Similarly, the levels of tPA, Plg and Pl in small intestine were higher than those in large intestine, but with respect to PAI-1 and alpha(2)PI, the matter was reverse. In addition, the fibrinolytic activity in muscle tissue was lower, however, the levels of tPA, Plg, and Pl in cardiac muscle were obviously higher than those in skeletal muscles, and the levels of PAI-1 and alpha(2)PI were significantly lower than those in skeletal muscle. Our data demonstrate that a remarkable difference of the fibrinolytic patterns exists in rabbit tissues, which has probable profound significance in understanding the relationship between the function of haemostasis or thrombosis and the physiologic function in tissues.

Maspin Binds to Urokinase-type and Tissue-type Plasminogen Activator through Exosite-Exosite Interactions

Maspin is a member of the serpin family with a reactive center loop that is incompatible with proteinase inhibition by the serpin conformational change mechanism. Despite this there are reports that maspin might regulate uPA-dependent processes in vivo. Using exogenous and endogenous fluorescence, we demonstrate here that maspin can bind uPA and tPA in both single-chain and double-chain forms, with K(d) values between 300 and 600 nM. Binding is at an exosite on maspin close to, but outside of, the reactive center loop and is therefore insensitive to mutation of Arg(340) within the reactive center loop. The binding site on tPA does not involve the proteinase active site, with the result that maspin can bind to S195A tPA that is already complexed to plasminogen activator inhibitor-1. The ability of maspin to bind these proteinases without involvement of the reactive center loop leaves the latter free to engage in additional, as yet unidentified, maspin-protein interactions that may serve to regulate the properties of the exosite-bound proteinase. This may help to reconcile apparently conflicting studies that demonstrate the importance of the reactive center loop in certain maspin functions, despite the inability of maspin to directly inhibit tPA or uPA catalytic activity in in vitro assays through engagement between its reactive center loop and the active site of the proteinase.

Intracerebral Hematoma Lysis

Object Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model. Methods Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed. The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (±standard error of the mean [SEM]) thrombus volume of 1.43 ±0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (±SEM) thrombus volume of 19.99 ±3.74 mm3 (p &lt;0.001). Conclusions Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.

Dihydropyridine Calcium Antagonists Increase Fibrinolytic Activity: A Systematic Review

Calcium antagonists have been shown to be superior over other antihypertensive drugs to prevent stroke. Because this cannot be fully attributed to blood pressure lowering effects, other mechanisms seem to play a role. Previously we found in patients with subarachnoid hemorrhage that nimodipine enhances fibrinolytic activity. The purpose of this systematic review was to investigate the fibrinolytic effect of calcium antagonists in general, especially in patients with hypertension. We systematically studied the entire PUBMED and EMBASE database with the search terms 'calcium antagonist' combined with 'fibrinolysis', '(euglobulin) clot lysis time' (ECLT), 'tissue plasminogen activator' (tPA), or 'plasminogen activator inhibitor' (PAI). Twenty-six prospective studies were identified and 22 manuscripts were included (802 investigated individuals). The results show that calcium antagonists significantly increase fibrinolysis as shown by a reduction of the ECLT standardized mean differences (SMD) -0.58 (95% confidence interval (CI) -1.05 to -0.11)) and an increase of tPA activity (SMD 0.73 (95% CI 0.25 to 1.21)). This increase of fibrinolysis is apparently caused by an increase of the tPA antigen level (SMD 0.16 (95% CI -0.05 to 0.37)) and a decrease of the plasminogen activator inhibitor-1 antigen antigen (SMD -0.36 (95% CI -0.74 to 0.02)). A sensitivity analysis showed that dihydropyridines, but not phenylalkylamines, exert a fibrinolytic effect. This fibrinolytic effect is not only seen in patients with subarachnoid hemorrhage but also in hypertensive patients. In conclusions, calcium antagonists increase fibrinolytic activity. This may add to the beneficial pharmacological effect of calcium antagonists to prevent ischemic events in patients with hypertension and subarachnoid hemorrhage.

Scar Formation

Injured tissue produces fibrin, which makes a provisional extracellular matrix (ECM). Degradation of this fibrin ECM by plasmin is required for minimizing scar formation. Plasmin is produced by proteolytic cleavage of plasminogen by plasminogen activators (tPA and uPA), which are inhibited by plasminogen activator inhibitor-1 (PAI-1). Sachs et al . find that mice deficient in p75 neurotrophin receptor (p75 NTR ) exhibit reduced fibrin deposition after sciatic nerve crush injury or lipopolysaccharide-induced pulmonary fibrosis. The decrease in fibrin associated with sciatic nerve injury was due to increased expression and activity of tPA, whereas the decrease in fibrin associated with pulmonary fibrosis was due to decreased PAI-1 abundance. In wild-type mice after sciatic nerve injury, Schwann cells in which p75 NTR was abundant lacked tPA, which suggests that cells expressing p75 NTR did not express tPA. The increased proteolytic activity toward fibrin (measured by in situ zymography) associated with the nerve injury in p75 NTR −/− mice was prevented by application of a specific inhibitor of tPA or by crossing the mice with tPA −/− mice to produce mice deficient in both tPA and p75 NTR . When cultured on a fibrin gel, Schwann cells from the p75 NTR −/− mice degrade the fibrin, whereas wild-type Schwann cells form a monolayer. Studies with a transfected fibroblast cell line overexpressing p75 NTR showed increased abundance of transcripts for PAI-1 and decreased transcripts and activity of tPA. Transcriptional regulation of tPA required a cAMP (adenosine 3′,5′-monophosphate) pathway. Inhibition of tPA activity in the p75 NTR -overexpressing cells was prevented if cAMP concentrations were increased pharmacologically and cAMP concentrations were decreased in the p75 NTR -overexpressing cells. The injured sciatic nerves also showed increased cAMP in the p75 NTR −/− mice compared with injured nerves from wild-type mice. Coimmunoprecipitation studies and in vitro interaction studies indicated that p75 NTR and phosphodiesterase 4A5 (PDE4A5) interacted. The authors propose that recruitment of PDE4A5 to the membrane inhibited cAMP signaling, a hypothesis supported by decreased activation of a plasma membrane protein kinase A reporter in the p75 NTR -overexpressing cells. Tissue remodeling and scar formation appear to be additional ways that p75 NTR signaling is involved in response to injury. B. D. Sachs, G. S. Baillie, J. R. McCall, M. A. Passino, C. Schachtrup, D. A. Wallace, A. J. Dunlop, K. F. MacKenzie, E. Klussmann, M. J. Lynch, S. L. Sikorski, T. Nuriel, I. Tsigelny, J. Zhang, M. D. Houslay, M. V. Chao, K. Akassoglou, p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J. Cell Biol. 177 , 1119-1132 (2007). [Abstract] [Full Text]