Platelet serotonin transporter in stroke patients.

OBJECTIVES: Post-stroke depression can be treated with serotonin transport inhibitors suggesting a role for the serotonin system in these patients. The number of platelet serotonin transporters in stroke patients and in control subjects have been measured in this study. MATERIAL AND METHODS: Newly admitted stroke patients who did develop or who did not develop a post-stroke depression, non-acute patients who previously had had a stroke and control subjects were compared. The number of platelet serotonin transporters was analysed by ligand binding methodology. RESULTS: The number of platelet serotonin transporters was low shortly after a stroke compared with normal subjects; no difference was found between the stroke patients who developed a post-stroke depression and those who did not. CONCLUSION: A low number of platelet serotonin transporters may be a non-specific state marker for a condition as acute stroke.

Decreased reuptake of serotonin in human platelets after surgery.

We have documented earlier a decrease in platelet serotonin and a concurrent increase in plasma serotonin, 5-hydroxytryptamin (5-HT) after various forms of stress, suggesting a disturbed platelet 5-HT reuptake mechanism following stress. In order to further elucidate these findings, we have studied platelet 5-HT reuptake kinetics (Vmax and Km) in nine patients before and 4 days after major, uncomplicated abdominal surgery. We found a significant decrease in the maximal 5-HT reuptake velocity (Vmax) after surgery and changes in Km, verifying alterations in the affinity of the platelet 5-HT transport system. The present results thus confirm the hypothesis that 5-HT reuptake kinetics are altered following adrenergic hyperactivity. A decrease in platelet 5-HT reuptake may bear implications for our understanding of poststress adaptive changes in the cardiovascular system as well as in the central nervous system (CNS) serotonergic neurones following stressful stimulation.

Serotonin metabolism in chronic tension-type headache.

Serotonergic neurons play a major role in the regulation of pain and may therefore also be involved in the pathophysiology of tension-type headache. Platelets are important in the regulation of the free serotonin level in plasma and may be a model of serotonergic neurons. The aim of the present study was to investigate the peripheral serotonin (5HT) metabolism in patients with chronic tension-type headache. The 5HT levels in platelets and in plasma, the beta-thromboglobulin (beta-TG) levels in plasma, and the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) were measured in 40 patients with chronic tension-type headache and in 40 healthy controls. The platelet uptake index was calculated as the ratio between platelet 5HT and plasma 5HT levels. There were no significant differences in platelet 5HT, plasma 5HT, beta-TG, or 5HIAA between patients and controls. The platelet uptake index was significantly lower in patients 243 (136-367) than in controls 352 (202-508), p=0.03. Our results indicate that the peripheral 5HT metabolism is largely normal in patients with chronic tension-type headache.

Subarachnoid bupivacaine increases human cerebrospinal fluid concentration of serotonin.

BACKGROUND AND OBJECTIVES: Serotonin (5-hydroxytryptamine [5-HT]) has antinociceptive properties at the spinal level. Activation of descending serotonergic neurons or topically applied 5-HT at the spinal cord inhibits rostral spread of sensory information. Epidural anesthesia has been shown to increase 5-HT in plasma, and local anesthetics may interfere with 5-HT reuptake and metabolism. For these reasons, the action of subarachnoid local anesthetics on cerebrospinal fluid (CSF) 5-HT concentrations has been studied. METHODS: Six volunteers received lumbar spinal anesthesia with 0.5% bupivacaine through subarachnoid catheters, and CSF and plasma 5-HT concentrations were determined radioenzymatically before and after anesthesia. RESULTS: Plasma 5-HT was unchanged, but CSF 5-HT increased by 300% after bupivacaine administration (P < .02). CONCLUSION: Subarachnoid bupivacaine increases local 5-HT concentration. This may have implications for nociceptive gating as well as for local vasoregulation.

Purine metabolite washout and platelet aggregation at reflow after tourniquet ischemia: effect of intravenous regional lidocaine.

Tourniquet ischemia will influence the biochemical milieu of tissue cells and affect the metabolism of purines in skeletal muscle distal to the occlusion. At reperfusion, generation of oxygen radicals by the hypoxanthine-xanthine oxidase system may ensue, influencing white blood cell and thrombocyte aggregation, causing damage to the endothelial cell barrier and inducing non-reflow type phenomena. Amide-type local anaesthetics are known to affect local vasotone, leukocyte adherence and platelet function but the influence of lidocaine on purine metabolite washout and platelet aggregation following tourniquet ischemia for lower limb surgery is not known in detail. Therefore, the effects of regional intravenous lidocaine during tourniquet ischemia for knee surgery on purine catabolite washout and platelet function following reflow were assessed. Eight patients served as control (C-group) and 8 (L-group) received 100 ml of lidocaine (2.5 mg/ml) in the emptied venous bed of the leg to be operated. All patients had spinal anaesthesia (0.5% bupivacaine). Effluent venous blood from the leg and radial arterial blood was collected and analysed for xanthine (X), hypoxanthine (HX), base excess (BE), pH and potassium before and after reperfusion. Platelet ADP-induced aggregation (ADP-agg.) and secretion of beta-thromboglobulin (beta-TG) were measured in the effluent blood as well as systemically. After tourniquet release (TR), X and HX were significantly increased in effluent venous blood but the washout was enhanced in the L-group during the initial reperfusion phase. BE was significantly higher in the L-group both before and after TR whereas pH and potassium washout was comparable between the groups. No systemic effects on platelets were detected after tourniquet release but ADP-agg. in effluent venous blood was attenuated in 6 out of 8 patients in the L-group (NS). It is concluded that HX and X are generated during leg ischemia. Regional intravenous lidocaine, most probably through a vasodilatory mechanism and inhibition of white blood cell activation, may attenuate non-reflow phenomena and thereby exert beneficial effects on post-ischemic recovery by enhancing post-ischemic tissue reperfusion.

Psychopathology measured by established self-rating scales and correlated to serotonin measures in patients with fibromyalgia.

The objective of the study was to evaluate the presence of psychopathology in fibromyalgia patients compared to a control group of rheumatic patients with pain. Forty-nine fibromyalgia patients and 33 controls were evaluated using established self-rating scales. Serotonin was determined using a radioenzymatic method. Fibromyalgia patients scored significantly higher than the controls on the majority of the subscales on the SCL-90, the two subscales on the Spielberger State and Trait Anxiety Inventory, the GHQ 12 scale and on a visual analogue pain scale. In a multivariate analysis the somatization dimension followed by the state anxiety accounted for the highest difference. Platelet-poor plasma serotonin, platelet serotonin and platelet uptake index were not significantly different between the groups. In conclusion, fibromyalgia patients presented quantitatively more psychopathology than the control group on a wide range of psychopathologic axes, and this cannot solely be accounted for by their higher level of pain.

Platelet activation in major surgical stress: influence of combined epidural and general anaesthesia.

Platelets are activated in surgery releasing vasoactive substances such as serotonin and thromboxane. Platelets become temporarily hypoaggregable during surgery followed by a postoperative hyperaggregability. Local anaesthetics are known to inhibit platelet function but earlier reports are conflicting. In order to study the impact of the combined use of general and regional anaesthesia on platelet function during major surgery 16 otherwise healthy patients were randomised to either general anaesthesia (GA) (n = 8) or GA combined with epidural anaesthesia (GA+EPI) (n = 8) for elective upper abdominal surgery. Cyclic 3',5' adenosine monophosphate, plasma glucose, plasma cortisol and the rate pressure product (RPP) were markers of the stress response. ADP-induced platelet aggregation and the release products beta-thromboglobulin, serotonin and thromboxane 2 were measured in plasma before and during as well as for 3 days after surgery. A marked stress response was noted in both groups and epidural anaesthesia (EPI) only reduced the rate pressure product (RPP). Platelet aggregation was reduced during surgery, a little more so in the GA+EPI group. Postoperatively both groups showed significant hyperaggregability. The release products were not significantly influenced by regional anaesthesia. In conclusion epidural as combined with general anaesthesia affects platelet responses to major abdominal surgery only to a minor extent, although it may attenuate the haemodynamic response.

Epidural anaesthesia prolonged into the postoperative period prevents stress response and platelet hyperaggregability after peripheral vascular surgery.

The occlusion rate of peripheral vascular grafts depends on technical as well as endogenous factors. Platelets play an integral part in graft failure and it has been suggested that anaesthesia may influence platelet function. In order to evaluate the influence of anaesthesia on stress response and platelet function in peripheral vascular surgery, patients (n = 18) were allocated to either general anaesthesia (GA; n = 9) followed by alleviation of postoperative pain with intramuscular analgesics or to lumbar epidural anaesthesia (EPI; n = 9) which was continued for 24 hours postoperatively. Before, during, as well as after vascular surgery of the lower extremity plasma levels of cortisol, glucose, serotonin (p-5HT), and urinary 5-hydroxyindole-3-acetic acid (5-HIAA) were analysed and platelet aggregability was determined. In the GA group surgery was accompanied by a significant stress response while in the EPI group this stress response was almost completely abolished. Platelet aggregability was reduced intraoperatively in both groups but in the postoperative period there was a marked hyperaggregability only in the GA group. P-5HT was increased preoperatively in both groups but was not affected by surgery. It is concluded that epidural anaesthesia, due to its effects on platelet aggregability, may be advantageous for peripheral vascular surgery.

Plasma serotonin increase during episodes of tension-type headache.

The mechanisms of tension-type headache remain to be determined. Biochemical abnormalities have been rarely demonstrated. We performed a controlled study of 5-hydroxytryptamine (5HT) in platelet poor plasma obtained from 13 female patients during and between episodes of tension-type headache. The 5HT concentration in patients free of headache was not different from controls, whereas a significant increase in 5HT concentration was seen during headache (p < 0.02). This finding is attributed to release of 5HT from platelets or disordered 5HT metabolism during headache attacks, possibly related to pain in the latter case. We conclude that 5HT may be involved in the pathogenesis of tension-type headache but by different mechanisms than migraine.

General versus regional anaesthesia and platelet aggregation in minor surgery.

In order to evaluate the impact of minor surgery on platelet aggregability and the effect of anaesthesia on this parameter, we allocated 14 otherwise healthy men for inguinal herniotomy to either general anaesthesia (n = 7) or lumbar epidural anaesthesia (n = 7). Platelet aggregation threshold to adenosine diphosphate (ADP-threshold) was measured before and after anaesthesia, prior to surgery, at the end of surgery and during the following hours as well as on the first post-operative morning. General anaesthesia did not affect ADP-threshold while epidural analgesia itself induced a significant increase. During and soon after surgery the ADP-threshold increased in those receiving general anaesthesia while in those receiving epidural analgesia the ADP-threshold returned to pre-operative levels. On the first post-operative morning both groups showed a significantly lower ADP-threshold as compared to the pre-operative level. Surgery induced an increase in 3'5' cyclic-adenosine monophosphate (cAMP). This adrenergic response was attenuated by epidural analgesia.

Effect of supine exercise on platelet aggregation and fibrinolytic activity.

In 12 healthy young men, strenuous cycling exercise in the supine position, caused platelet aggregability to decrease and the ADP threshold to rise from 7.0 microM resting, to 9.5 exercising (P < 0.01). At the same time, fibrinolytic activity increased markedly: euglobulin clot lysis time shortened from 178 to 68 min, PAI-1 fell from 8.91 to 5.16 IU ml-1, and t-PA rose from 0.56 to 3.95 IU ml-1, all three values were significant to P < 0.01. When the erect posture was assumed after lying at ease for 1 h after exercise, it did not increase platelet activity as expected, but caused a modest increase of fibrinolytic activity. These results suggest that supine exercise will not affect the haemostatic system adversely.

Effect of nitrous oxide and volatile anaesthetics on platelet function in man.

Twelve otherwise healthy male volunteers scheduled for arthroscopy of the knee were studied. The influence in vivo of nitrous oxide (N2O) per se and the addition of a halogenated volatile anaesthetic (halothane or isoflurane) on ADP-induced platelet aggregation and release of beta-thromboglobulin into plasma was evaluated. All measurements were made before surgery. We found that N2O increased platelet aggregation. Adding a halogenated anaesthetic reversed the relative hyperaggregation induced by N2O. The concentrations in plasma of the platelet release product beta thromboglobulin were not influenced by the anaesthetics.

Platelet activation in mental stress.

Platelets are known to become activated in vivo by different stressful stimuli such as surgery and dynamic exercise. Mental stress has been shown to increase platelet aggregability. Platelet activation is thought to be of major importance in atherogenesis and cardiac fatalities. In order to clarify further stress-induced platelet activation with special reference to the period after the stress, we studied eight young, healthy volunteers during and for 1 h after a mental stress test (Stroops Colour Word Conflict Test). Using highly standardized techniques, we have measured platelet aggregability ex vivo and the platelet release products beta-thromboglobulin, platelet factor 4 and serotonin in plasma. As markers of the stress response we measured cyclic-AMP in plasma, heart rate, cardiac output and blood pressure. The stress test induced a significant cardiovascular response with increases in heart rate, blood pressure, and cardiac output and as a measure of adrenergic activity an increase in cyclic AMP in plasma during the test. Platelet aggregability was unaffected during the test but decreased following the stress. During the first hour following the test and release products beta-thromboglobulin and serotonin increased significantly in plasma. We conclude that platelets are activated during mental stress and that this activation involves a post-stress release of vasoactive compounds from platelets.

Serotonin concentrations in plasma and variations during the menstrual cycle.

We used a specific and sensitive radioenzymatic method to establish a reference interval for the concentration of serotonin in platelet-poor plasma in 98 healthy volunteers (49 men, 49 women). The interval was 0-11 nmol/L with a median of 2.8 nmol/L. No difference in concentration in relation to sex or age was observed. In a group of eight very old volunteers (ages 86-92 years), however, concentrations were increased. In addition, we monitored the plasma concentrations of serotonin in 20 healthy women (ages 26-45 years) through two menstrual cycles. Periovulatory and premenstrual concentrations were greater than the serotonin concentration at the start of menstruation.

Platelet responses to intravenous infusion of Intralipid in healthy volunteers.

Platelet function and morphology were studied in eight healthy male volunteers before, immediately after, and 1 d after the infusion of 250 mL of 10% Intralipid. The plasma concentrations of the platelet-release products beta-thromboglobulin (beta-TG), serotonin (5-HT), and platelet factor 4 (PF4) and the threshold to ADP- and adrenaline-induced aggregation were determined ex vivo. In addition the platelets were examined by electron microscopy. Although platelets released beta-TG, PF4, and 5-HT after the infusion, there was no significant change in ex vivo aggregability. About 3% of the platelets had internalized small-sized lipid particles (0.1-0.2 micron) whereas no other morphological changes were detected. The release products may negatively affect the hemorheological properties of the microcirculation in critically ill patients. The release of PF4 may explain the antiheparin effect of parenteral lipid therapy.

Post-exercise platelet activation--aggregation and release in relation to dynamic exercise.

Relatively scarce information is found on the period immediately following physical stress, with special reference to human platelet activity. This, in connection with earlier observations of an increase in platelet release products and hyperaggregability following surgical stress, has initiated the present study. We studied platelet function in eight healthy non-mediated volunteers during and 1 h after cycle exercise of submaximal intensity. ADP-induced platelet aggregability was enhanced in the last minute of exercise followed by a decreased aggregability 1 h after. Adrenaline-induced platelet aggregation showed the same attenuation after exercise but no change during work. The release products beta-thromboglobulin and serotonin in plasma showed significant increases after exercise. This is taken as evidence of an enhanced platelet activity following exercise. A normal stress-response, measured as increase in cyclic AMP in plasma, was observed. In conclusion, platelets are activated following moderate exercise and it seems valid to include the post-exercise period in future studies.

Serotonin in nasal secretion.

The aim of this study was to investigate the serotonin content in nasal secretion. Histamine- and methacholine-induced nasal secretions were collected during a 5-min period after challenge in 33 normal subjects. Serotonin was determined radioenzymatically and was found in 66% of pure, blown secretions. The median concentration of serotonin in histamine- and methacholine-induced secretions was 6.3 nmol/l (range less than 1.6-52.0) and 2.3 nmol/l (range 1.6-140.0) (NS), respectively. The serotonin concentration in allergen-induced nasal secretions in 7 rhinitis patients was 0.8 to 159 nmol/l, median 10.4 nmol/l which did not differ from the serotonin levels in the normal subjects. The serotonin concentration in nasal lavage fluids in 5 subjects was low (below the detection limit in 78% of the samples). Further studies of serotonin in patients with nasal hypersecretion are indicated.

Effect of nasal allergen challenge on serotonin, substance P and vasoactive intestinal peptide in plasma and nasal secretions.

We have studied the changes in concentration of serotonin, substance P, and vasoactive intestinal peptide (VIP) in plasma following a nasal allergen provocation in 14 grass pollen-allergic subjects; in five the urinary excretion of serotonin and 5-hydroxy-indolyl-acetic acid (5-HIAA) was also measured. In addition, the concentration of serotonin and substance P was measured in nasal secretions following nasal challenge with allergen and methacholine. The results showed an allergen-induced increase in free plasma serotonin (P less than 0.01) and no change in platelet serotonin, urinary serotonin and urinary 5-HIAA. The plasma substance P level tended to fall (P greater than 0.1), while plasma VIP increased significantly (P less than 0.02). In nasal secretions, there were measurable levels of serotonin in all samples and of substance P in all but one. There was no difference between the concentrations of serotonin and substance P in secretions collected after allergen challenge and after methacholine challenge. For both substances, the secretion median value was comparable to that of plasma. Symptom reduction by topical and systemic pretreatment with a serotonin- and VIP-antagonist before nasal allergen provocation is necessary to define the role of these two agents in allergic rhinitis.