M.H. Pietraszek

Blood serotonergic mechanisms in type 2 (non-insulin-dependent) diabetes mellitus

Serotonin (5-hydroxytryptamine, 5HT) is believed to play a role in vasospasm and increased platelet aggregability that in turn could contribute to atherosclerosis. The present study was designed to evaluate a possible participation of serotonin in the development of vascular complications in diabetes mellitus. Whole blood and plasma serotonin, the platelet uptake and release of the amine and serotonin- induced platelet aggregation were studied in 32 patients with Type 2 diabetes. The patients were divided into three groups according to the presence and advancement of retinopathy. Mean levels of blood serotonin content were significantly lower in diabetic patients. The concentration of the amine in the plasma was markedly increased in diabetes. It was correlated with vascular changes of the retina. We established that platelets from diabetic patients took up less serotonin when compared to the control group. Concomitantly enhanced spontaneous release of 5HT from platelets was observed. The platelets of diabetic patients showed increased response to serotonin. There was a relation between serotonin-induced aggregation and the presence of retinopathy. These results suggest that serotonin may be involved in the pathogenesis of diabetic vasculopathy.

Relationship between serotonergic measures in periphery and the brain of mouse

Circadian rhythm and the relationship between the concentration of serotonin (5HT) and related substances (5-hydroxyindoleacetic acid; 5HIAA and tryptophan; Trp) in mouse brain, stomach and blood have been studied. All factors underwent circadian changes in the brain and blood. 5HT and 5HIAA levels in the stomach showed no circadian fluctuation. The concentrations of 5HT in the brain and blood did not correlate. Significant correlations were found between other serotonergic parameters analyzed in brain, stomach and blood. A significant negative correlation was observed between brain 5HIAA and blood 5HIAA. The concentration of tryptophan in the brain was correlated with the plasma total tryptophan level. There was fairly significant correlation (p less than 0.06) between brain serotonin and plasma tryptophan levels. The brain serotonin and tryptophan levels were strongly correlated (R = 0.410, p less than 0.03). Significant negative correlation was found between serotonin in the blood and serotonin in the stomach as well as between its level in the brain and in the stomach. The significance of these findings and their relationship to the use of peripheral serotonergic system as a model of neurons are discussed.

Plasminogen activators and plasminogen activator inhibitor 1 before and after venous occlusion of the upper limb in thromboangiitis obliterans (Buerger's disease)

Plasma levels of plasminogen activators (t-PA, u-PA) and their inhibitor (PAI-1) were studied in patients suffering from Buergers disease and healthy volunteers before and after 15 minutes of venous occlusion test. The baseline levels of t-PA in group of patients did not differ from those of controls. On the contrary patients with Burgers disease showed a marked increase in u-PA antigen concentrations with concomitant decrease in PAI-1 antigen levels. During venous stasis t-PA antigen concentrations increased in all subjects, however it was much pronounced in controls. Venous occlusion resulted in significant decrease in free PAI-1 levels in the group of patients only. In conclusion, Buergers disease is associated with the endothelial derangement with increased u-PA release and decreased PAI-1 release, which does not influence the function of fibrinolytic system. The fact that the reduced response of the endothelium to release t-PA after venous stasis goes in parallel with marked decrease in PAI-1 antigen levels seems to suggest that patients suffering from Buergers disease are not at high risk of intravascular fibrin deposition.

Correlation between serotonergic measures in cerebrospinal fluid and blood of subhuman primate

The relationship between the concentration of serotonin (5-hydroxytryptamine; 5-HT), its precursor; tryptophan (Trp) and the main metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and blood of monkey have been studied. 5-HT, Trp and 5-HIAA underwent circadian changes in both CSF and blood. Significant correlations were found between 5-HT, 5-HIAA and Trp in CSF and blood. The significance of these findings and their relationship to the use of peripheral serotonergic system as a functional model of the central nervous system are discussed.

The effect of MCI-9042 on serotonin-induced platelet aggregation in type 2 diabetes mellitus

MCI-9042, a potent inhibitor of 5HT2 receptor, was used to examine its effects on serotonin induced-aggregation of platelets obtained from patients with type 2 diabetes mellitus (DM). The extent of platelet aggregation induced by serotonin increased in DM patients without retinopathy, but the increase was further significant in DM patients with retinopathy. MCI-9042 as well as ketanserin, inhibited significantly serotonin induced-aggregation of platelets obtained from DM patients with retinopathy. MCI-9042 dose dependently inhibited platelet aggregation induced by serotonin and collagen. These results suggest that serotonin which may be released from platelets of DM patients may activate platelets together with collagen exposed on atherosclerotic endothelium and that MCI-9042 may be inhibitory to enhanced platelet aggregability under these conditions.

Fibrinolytic activity in depression and neurosis

It has been a long-established clinical and epidemiological observation that patients with affective disorders have a higher than expected rate of mortality from cardiovascular disease (1,2). Further evidence suggests that major depression has a direct negative impact on the outcome of cardiovascular disease (3’1. The mechanism through which mental disorder is a cause of cardiovascular death in depressed patients and affects outcome in cardiac disease is far from clear. The fibrinolytic system plays a key role in defence against fibrin deposition on the vessel wall and is thus an essential protection against blood vessel occlusion. Decreased fibrinolytic activity is considered to be a factor involved in the pathogenesis of myocardial infarction, cerebral thrombosis and deep vein thrombosis. It seemed, therefore, of interest to evaluate the function of the fibrinolytic system in patients suffering from depression and neurosis using a newly developed assay for the determination of plasma plasminogen activators and inhibitors (4).

Diurnal patterns of serotonin, 5-hydroxyindoleacetic acid, tryptophan and fibrinolytic activity in blood of depressive patients and healthy volunteers

Diurnal changes of serotonin-related factors in whole blood and fibrinolytic activity were determined in depressed patients and healthy controls. Whole blood serotonin concentration of depressed patients showed marked changes throughout daytime, with maximum values in the evening and lowest values in the morning, whereas its metabolite 5-HIAA followed a contrary pattern. The circadian rhythm of 5-HT and 5-HIAA in the control group was quite different from depressed patients. Plasma levels of tPA decreased from 12:30 to 16:30. Concentrations of free plasminogen activator inhibitor (PAI-1) and complex of tPA-PAI-1 decreased from 8:30 to 16:30. Plasma levels of total PAI-1 decreased from 8:30 to 16:30. Plasma levels of the fibrinolytic parameters may be lower in depressive patients than in normal controls. These results support the changes in the circadian rhythm of serotonin and its related substances in the blood of depressive patients.

Fibrinolysis and serotonin under cyclosporine A treatment in renal transplant recipients.

Cyclosporine A (CyA), a potent immunosuppressive drug, has been used in renal transplant recipients with increasing frequency since 1982. Despite its efficacy, CyA therapy has been associated with an increased incidence of thromboembolic complications. This has been attributed to increased thromboxane production, reduced prostacyclin synthesis and increased platelet aggregability. The coagulation system is also altered in CyA-treated patients and some of these changes would favor thrombosis. Increased fibrinogen and FVII:C levels have also been associated with an enhanced risk of thrombosis. In contrast, CyA therapy was reported to increase the levels of antithrombin III and protein C, two proteins known to protect against venous thromboembolism. However, the possible effect of CyA on the fibrinolytic system has not been thoroughly investigated and rather confusing data have been reported concerning both enhancement and suppression of fibrinolysis. Serotonin (5-hydroxytryptamine, 5-HT) may play a role in hemostasis and platelet/vessel wall interactions. It may facilitate platelet thrombus formation by potentiating the aggregatory response to other agents such as ADP, collagen or epinephrine and by causing vasoconstriction. Taking all these data into consideration we have measured some fibrinolytic parameters, whole blood and plasma serotonin concentration in cyclosporine A- and non-cyclosporine A-treated kidney transplant recipients.

Endothelins inhibit serotonin-induced platelet aggregation via a mechanism involving protein kinase C

Endothelins are a family of three peptides that act as local hormones released by the endothelium. They were found to inhibit rabbit and dog platelet aggregation in vivo, but no effect was observed in vitro. In order to investigate the possible interaction between endothelins and human platelet serotonin receptors, their effects on platelet aggregation induced by serotonin was studied. Endothelin-1, -2 and -3 had a dual action, on platelet aggregation and calcium mobilization induced by serotonin. When added at the same time as serotonin, endothelin potentiated the response to the amine. On the contrary, preincubation of platelet suspension with endothelin resulted in a concentration-dependent inhibition of the serotonin-mediated platelet response. Moreover, endothelin-1 inhibited serotonergic amplification of epinephrine-induced aggregation of platelets. We hypothesize that endothelins can bind to the platelet membrane and interact with serotonin receptors. The diverse effect of endothelins on serotonin-induced aggregation and calcium mobilization may be due to stimulation of protein kinase C.

Serotonergic measures in cyclosporine a treated rats

Whole blood and plasma serotonin (5-HT), its major metabolite--5-hydroxyindoleacetic acid (5-HIAA), renal cortical blood flow, serum creatinine and whole blood cyclosporine A (CyA) levels were investigated in rats administered with CyA at a dose of 5 mg/kg b.w. or 10 mg/kg b.w. for 14 consecutive days. Serum creatinine remained unaltered during CyA treatment and no apparent changes in excised kidneys were found. Dose-dependent increases in whole blood and plasma 5-HT as well as whole blood 5-HIAA levels were observed. Renal cortical blood flow declined significantly and correlated inversely with whole blood 5-HT and 5-HIAA as well as with plasma 5-HT. Whole blood 5-HT was positively related to whole blood CyA levels. Taking all these data into account and considering the fact that 5-HT is a potent vasoconstrictor, a possible role of this amine in the pathogenesis of renal ischemia during CyA administration is suggested.