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PubMed1998

Ultrastructural evidence of distinctive behavior of L-selectin and LFA-1 (alphaLbeta2 integrin) on lymphocytes adhering to the endothelial surface of high endothelial venules in peripheral lymph nodes.

Using an immunoelectron microscopic technique, we demonstrated the distinctive localization of L-selectin, alphaL and beta2 integrins (LFA-1) on lymphocytes adhering to high endothelial venules (HEVs) of peripheral lymph nodes. Immunogold staining clearly demonstrated the preferential localization of L-selectin on the faintly adherent microvilli to endothelial surfaces. Often, the particles of L-selectin were found around those microvilli with a dispersed distribution. Examination by antibody-coated latex beads showed that the localization of L-selectin was not restricted to the lymphocyte surface but also found on endothelial cells. These data suggest the molecular shedding from lymphocytes and its transfer to the HEV surface as the 'molecular footprints' of rolling cells. Concomitant with the dispersion of L-selectin, the gold particles of alphaL, and beta2 integrins showed significant capping and clustering images on the adherent border of lymphocytes. This redistribution of LFA-1 may be important for inducing the transition of the molecule into the active state to facilitate effective binding to its endothelial ligands. These morphological findings revealed the characteristic behavior of L-selectin and LFA-1 on lymphocytes, and they confirm their respective molecular roles in the current adhesion cascade model between lymphocytes and HEVs.

Animals↗
PubMed2005

High activity of acid sphingomyelinase in major depression.

Acid sphingomyelinase (A-SMase) and its reaction product ceramide may play a role in the pathophysiology of depressive disorders and in the therapeutic action of antidepressive drugs. In a prospective case-control study, A-SMase activity was measured in peripheral blood mononuclear cells of 17 patients with a major depressive episode who were free of antidepressant drug therapy for at least 10 days and 8 healthy volunteers. In the patient group, A-SMase activity was correlated to the score (n=17, r=0.64, P=0.005). The patient group exhibited higher A-SMase activity compared to healthy volunteers (T=2.09, df=21.33, P<0.05). In addition, we demonstrate that the antidepressants imipramine and amitriptyline induce a long-term reduction of the activity of A-SMase in cultured cells.

Adult↗
PubMed2004

Effect of oxidized fibrinogens on blood coagulation.

We studied the effect of UV-irradiated fibrinogen on blood coagulation. Fibrinogen with oxidation degree of 10% moderately activated the intrinsic pathway, but inhibited the extrinsic pathway of blood coagulation. Fibrinogen with oxidation degree of 20% inhibited both the extrinsic and intrinsic blood coagulation pathways. We revealed disturbances in the formation of fibrin clot with oxidized fibrinogen, suppression of platelet aggregation mediated by collagen receptors, and inhibition of aggregation associated with von Willebrand factor activity. ADP initiated platelet aggregation, which was in direct proportion to the degree of fibrinogen oxidation. Our results indicate that oxidized fibrinogen produces a dysregulatory effect on platelets.

Blood Coagulation↗
PubMed1986

Calcium-blocker withdrawal phenomenon: increase in affinity of alpha 2 adrenoceptors for agonist as a potential mechanism.

Precipitation of myocardial ischemia after withdrawal of calcium channel blocking drugs has been observed in some patients, but the mechanism of this phenomenon is not known. Among 15 patients with coronary artery disease who had been treated with nisoldipine, onset of severe unstable angina was observed in 2 and evolution of acute myocardial infarction in 1 patient after abrupt withdrawal of nisoldipine therapy. To determine a mechanism of myocardial ischemia after cessation of nisoldipine therapy, the status of alpha 2 adrenoceptors and platelet sensitivity to epinephrine was examined in 5 patients. After 6 weeks of therapy, there were no changes in the number of alpha 2 adrenoceptors (199 +/- 45 vs 188 +/- 35 fmol/mg protein, mean +/- standard error of the mean) or affinity for antagonist (dissociation constant 5.78 +/- 0.99 vs 4.70 +/- 0.87 nM), but there was a significant (p less than 0.01) increase in the affinity of alpha 2 adrenoceptors for agonist epinephrine. In vitro platelet sensitivity to epinephrine, but not ADP, also increased markedly. It is postulated that an increase in alpha 2-adrenoceptor affinity for agonist may relate to platelet hyperactivity, which may result in severe myocardial ischemia upon withdrawal of calcium blocking drugs in some patients.

Adult↗
PubMed1989

Inhibition of cyclic AMP phosphodiesterase activity of human blood platelet membrane by ADP.

Purified human blood platelet membrane showed the presence of one low Km (1.1 microM) and one high Km (5.0 microM) cyclic AMP phosphodiesterase(s). Incubation of platelet-rich plasma or gel-filtered platelets with ADP (4.0 microM), a well-known platelet aggregating agent, resulted in the inhibition of phosphodiesterase activity of the isolated membrane by 25% in 5 min at 23 degrees C. A Lineweaver-Burk plot of the enzymic activity of the membrane preparation showed that ADP specifically inhibited the low Km (1.1 microM) phosphodiesterase by reducing the Vmax from 241 to 176 pmol/mg per min with concomitant lowering of Km to 0.5 microM. In contrast, neither the high Km (5.0 microM) enzymic activity of the membrane preparation nor the phosphodiesterase activities of the cytosolic fraction of the ADP-treated platelets was affected. This effect of ADP, which was independent of platelet aggregation, reached maximal level within 5 min of incubation. When platelet-rich plasma was incubated longer in the presence of nucleotide, the inhibition of phosphodiesterase activity began to decrease, and after 20 min of incubation approx. 90% of the original enzymic activity was regained. The incubation of platelet-rich plasma with 4.0 microM ADP also increased the cyclic AMP level to twice the basal level. The effect of ADP on the phosphodiesterase activity could be demonstrated only by incubating the intact platelets with the nucleotide. The treatment of isolated membrane from platelets, previously unexposed to ADP, with the nucleotide did not inhibit the enzymic activity. The inhibition of phosphodiesterase by the nucleotide in the absence of stirring, as expected, resulted in the inhibition of platelet aggregation when these cells were subsequently stirred with 1-epinephrine or an increased concentration of ADP.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Alpha-adrenoceptor-mediated actions of optical isomers and desoxy analogs of catecholimidazoline and norepinephrine in human platelets: in vitro.

Adrenoceptor-mediated effects of the enantiomers of optically active imidazoline, 2-(3,4,alpha-trihydroxybenzyl imidazoline (catecholimidazoline; CI), and norepinephrine (NE), and the corresponding desoxy derivatives, 2-(3,4-dihydroxybenzyl)imidazoline (desoxy-CI) and dopamine, have been investigated in human platelets. Differences between responsiveness of platelets from donor to donor were observed in the presence of the isomers and the desoxy analogs of NE and CI. In certain platelet preparations, all compounds gave concentration-dependent stimulatory responses, whereas in other preparations, only R(-)-NE and R(-)-CI were inducers of platelet aggregation and serotonin release. The rank order of stimulatory potencies (EC50; microM) for CI and NE was R(-)-NE (1.3) greater than R(-)-CI (7.5) greater than S(+)-NE (19) = S(+)-CI (20) = dopamine (22) greater than desoxy-CI (greater than 35). Unlike R(-)-CI, both S(+)-CI and desoxy-CI were either agonists or antagonists of human platelet function. In preparations unresponsive to the S(+)-isomers or desoxy analogs, the potencies (EC50) for R(-)-NE and R(-)-CI were 1.7 and 7.7 microM respectively. The corresponding inactive CIs [S(+)-CI and desoxy-CI] were inhibitors of both primary and secondary phases of aggregation and serotonin release responses to R(-)-CI and R(-)-NE, respectively. In contrast, the aggregation responses to ADP, arachidonic acid or U46619 were not blocked by S(+)-CI or desoxy CI. The rank order of inhibitory potencies for selected alpha-adrenoceptor agents against R(-)-NE was phentolamine greater than clonidine greater than desoxy-CI greater than S(+)-CI. Moreover, the relative inhibitory potencies of phentolamine and desoxy-CI against aggregation responses to R(-)-NE and R(-)-CI, respectively, were the same. These results suggest that the enantiomers and desoxy derivatives of CI and NE mediate their effects in human platelets by an interaction with alpha-adrenoceptors; catecholamines and imidazolines interact with the same alpha-adrenoceptors in human platelets; the stereochemical requirements of both chemical classes for stimulatory activity in human platelets adhere to the Easson-Stedman hypothesis in this alpha 2-adrenoceptor system; and desoxy-CI possessed the highest potency as an antagonist of alpha-adrenoceptors which suggests that the hydroxy group at the benzylic carbon atom of these imidazolines may not be required for maximal binding to adrenoceptors in platelets.

Blood Platelets↗
PubMed1995

Cool perfusion solutions for skin flaps: a new mixture of pharmacological agents which improves skin flap viability.

This study tested the hypotheses that perfusion of cooled skin flaps with established organ preservation solutions improves their viability and that this improvement can be further enhanced by pharmacological manipulation. Rabbit epigastric skin flaps were perfused with different solutions before explantation and stored at 8 degrees C for 6 days. In the first part of the experiment, flap viability was assessed 7 days after reperfusion of the flap via microvascular anastomoses. The different solutions were heparinised blood, University of Wisconsin solution, two of its modifications, EuroCollins solution and a pharmacological mixture containing phosphoenolpyruvate, desferrioxamine, nitrendipine, dextran 70 and a platelet-aggregating factor receptor antagonist (WEB 2170). In the second part, biochemical parameters of skin were measured at various reperfusion times. Adenosine triphosphate (ATP), reduced glutathione (GSH), myeloperoxidase (MPO) and tissue water were assayed at 0, 1, and 24 h after reperfusion. In addition, plasma thromboxane (TXB2) was measured at 0, 30 and 60 minutes after reperfusion. The viability of flaps perfused with the mixture (81%) was significantly higher than that of any of the other groups (39% for controls, 38% for EuroCollins, 13% for UW solution, 27% and 31% for its modifications). ATP levels after reperfusion were higher in the mixture group than in UW-perfused group. GSH levels in the mixture group were also higher than in the UW group, indicating higher level of protection against oxidative stress during reperfusion. There were no differences in MPO levels. Thromboxane levels associated with UW-perfused flaps were significantly higher than those associated with any other perfusion solution. In conclusion, perfusion of a mixture of pharmacological agents targeting specific aspects of ischaemia/reperfusion injury improved the viability of skin flaps stored in the cold for 6 days, whereas standard organ preservation solutions failed to affect significantly skin flap survival.

Adenosine↗
PubMed1992

Characterization of alpha beta+ CD4- CD8- CTL lines isolated from mixed lymphocyte cultures of adult mouse spleen cells.

Several CD4- CD8- and CD4- CD8+ T cell lines and clones have been isolated from the same mixed lymphocyte cultures. They express the alpha beta T cell receptor, are CD3+, V beta 8- and heat stable antigen-, and exhibit highly specific cytolytic activity mapping to H2Db. However, monoclonal antibody against H2Db failed to block lysis by CD4- CD8- cytotoxic T lymphocytes (CTL). One possible explanation is that the "double negative" cytotoxic T lymphocytes may recognize H2Db in the context of other class I molecules (Qa/Tla). CD4 and CD8 could be detected on some lines cloned in high concentrations of EL4 supernatant and the cell surface expression was influenced by growth conditions. The alpha beta+ CD4- CD8- CTL described in this report are clearly different from the so-called "autoimmune double negatives" which suggests a function for them in normal immune responses.

Animals↗
PubMed1985

Alpha 2-adrenoceptor coupling to adenylate cyclase in adrenaline insensitive human platelets.

Coupling of the alpha 2-adrenoceptor to adenylate cyclase was assessed in platelets from 3 groups of subjects: normal controls and patients with myeloproliferative disorders whose platelets were either sensitive or specifically insensitive to the aggregatory effects of adrenaline. The ability of adrenaline to induce the formation of a complex between the alpha 2-adrenoceptor and the inhibitory guanine nucleotide binding protein was examined in all three groups by assessment of the effect of mono and divalent cations and Gpp(NH)p on the displacement of [3H]yohimbine binding to platelet membranes by adrenaline. Coupling to adenylate cyclase was also assessed in separate studies of the inhibition by adrenaline of PGE1 stimulated cyclic AMP accumulation in whole platelets. Both the formation of the ternary complex and the inhibition by adrenaline of cyclic AMP accumulation was not significantly different in platelets sensitive or insensitive to adrenaline. These results suggest that inhibition of cyclic AMP alone does not explain the mechanisms of adrenaline induced platelet aggregation.

Adenylyl Cyclases↗
PubMed1987

A low molecular weight brain substance interacts, similarly to clonidine, with alpha 2-adrenoceptors of human platelets.

In the present study, we explored the effects of a clonidine-displacing substance (CDS) which was isolated and partially purified from bovine brain. The low molecular weight brain substance competes with clonidine and rauwolscine in rat brain membranes, and mimics clonidine's inhibitory action in rat vas deferens. We find that CDS competes with [3H]rauwolscine-labeled alpha 2-adrenoceptors in human platelets. Further characterization of CDS in human platelets reveals that, like clonidine, it inhibits the epinephrine-induced aggregation, potentiates the ADP- and the collagen-induced aggregation however, by itself, CDS is unable to induce aggregation. Unlike clonidine, CDS does not affect the prostacyclin (PGI2)-stimulated cAMP accumulation in intact platelets. The presence of CDS in human plasma, as we have recently shown, implies a possible role of CDS in the regulation of platelet action.

Animals↗
PubMed1991

The biochemical and structural maturation of human skeletal muscle cells in culture: the effect of the serum substitute Ultroser G.

On the basis of the percentage creatine kinase-MM, human skeletal muscle cells cultured on growth and differentiation media containing the serum substitute Ultroser G reach a significantly higher maturation grade after 7 days of differentiation than cells cultured on serum-containing media. They also remain viable for longer periods. The myotubes are much longer, their nuclei are often localized in rows on the periphery, and they show cross-striation more frequently. The activities of creatine kinase, citrate synthase, cytochrome c oxidase, AMP deaminase, and phosphorylase are significantly higher. Extending the differentiation period to 3 weeks increases the maturation grade of the cultures and the activities of all the enzymes mentioned before, except phosphorylase. A correlation exists between the enzyme activities and the maturation grade of the muscle cells. The content of fatty acid-binding protein also increases significantly with the maturation grade in contrast to the palmitate oxidation rate. The AMP deaminase and creatine kinase activity and the percentage MM-type remain lower in cultured cells than in adult muscle and the hexokinase activity remains higher, but the other enzyme activities become comparable after 20 days of differentiation. The myotubes, derived from Ultroser G-containing culture media, show spontaneous contractions after 12 days and cross-striation after 20 days when immunostained for the M-subunit of creatine kinase. These cells possess clusters of acetylcholine receptors, but aggregation of desmin at the site of the clusters was never detectable. The possibility of cultivating muscle cells with a predictable maturation grade allows the study of muscle development and muscular diseases caused by differentiation defects or by deficiency of a maturation-dependent (iso)enzyme.

AMP Deaminase↗