Increased platelet activation in the chronic phase after cerebral ischemia and intracerebral hemorrhage.
(1/1005)
BACKGROUND AND PURPOSE: Enhanced thromboxane (TX) biosynthesis has previously been reported in the acute phase after ischemic stroke. We investigated whether enhanced urinary excretion of 11-dehydro-TXB2, a noninvasive index of platelet activation, was present in the chronic phase after a transient ischemic attack (TIA) or stroke, including intracerebral hemorrhage. METHODS: We obtained a single urinary sample from 92 patients between 3 and 9 months after onset of stroke or TIA. The urinary excretion of the major enzymatic metabolite of TXA2, 11-dehydro-TXB2, was measured by a previously validated radioimmunoassay. The excretion rates were compared with those of 20 control patients with nonvascular neurological diseases. RESULTS: Urinary 11-dehydro-TXB2 averaged 294+/-139, 413+/-419, and 557+/-432 pmol/mmol creatinine for patients with TIA, ischemic stroke, and intracerebral hemorrhage, respectively; the values were higher in all subgroups (P<0.01) than that in control patients (119+/-66 pmol/mmol). Increased 11-dehydro-TXB2 excretion was present in 59% of all patients, in 60% (P<0.001) of patients with TIA, in 56% (P<0.001) of patients with ischemic stroke, and in 73% (P<0.001) of patients with intracerebral hemorrhage. Atrial fibrillation, no aspirin use, and severity of symptoms at follow-up contributed independently to the level of 11-dehydro-TXB2 excretion in a multiple linear regression analysis. CONCLUSIONS: Platelet activation is often present in patients in the chronic phase after stroke, including those with intracerebral hemorrhage. Persistent platelet activation, which is associated with atrial fibrillation and poor stroke outcome, can be substantially suppressed by aspirin treatment. (+info)
Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans.
(2/1005)
1. The metabolic processes that occur around the tendon during mechanical loading and exercise are undescribed in man. These processes are important for understanding the development of overuse inflammation and injury. 2. A microdialysis technique was used to determine interstitial concentrations of glycerol, glucose, lactate, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) as well as to calculate tissue substrate balance in the peritendinous region of the human Achilles tendon. Recovery of 48-62 % (range) at rest and 70-77 % during exercise were obtained for glycerol, glucose and PGE2. 3. Six young healthy humans were studied at rest, during 30 min of intermittent static plantar flexion of the ankle at a workload corresponding to individual body weight, and during 60 min of recovery. Microdialysis was performed in both legs with simultaneous determination of blood flow by 133Xe washout in the same area, and blood sampling from the radial artery. 4. With exercise, the net release of lactate as well as of glycerol from the peritendinous space of the Achilles tendon increased 2-fold (P < 0.05). Furthermore a 100 % increase in interstitial concentration of PGE2 and TXB2 was found, but it was only significant for TXB2(P < 0.05). As peritendinous blood flow increased 2- to 3-fold during intermittent static contractions, this indicates also that the output of these substances from the tissue increased during exercise. 5. This study indicates that both lipid and carbohydrate metabolism as well as inflammatory activity is accelerated in the peritendinous region of the human Achilles tendon with dynamic loading. (+info)
Effect of bolus epinephrine on systemic hemodynamics in canine anaphylactic shock.
(3/1005)
OBJECTIVE: Epinephrine (Epi) is considered to be the drug of choice for anaphylactic shock (AS). However, the benefit of this drug on improving systemic hemodynamics in AS has never been shown. We used a canine ragweed model of AS to determine if an intravenous bolus of Epi hastened the recovery of hemodynamics and modified mediator release (Med) compared with no treatment (NT). METHODS: In one protocol (n = 8), the effects on hemodynamics of two intravenous doses of Epi (0.01 and 0.025 mg/kg) were examined for 3 h postshock in respective studies approximately three weeks apart under pentobarbital anesthesia in the same animal. In five other dogs, left ventricular (LV) mechanics were additionally determined by sonomicrometric techniques to determine changes in contractility as defined by the preload recruitable stroke-work (SW) relationship. RESULTS: Compared with NT values, Epi treatments produced only transient increases in mean arterial pressure (MAP) and cardiac output (CO) post-challenge. By 20 min postshock, CO in the Epi studies were generally lower (p < 0.05) and BP was not different from NT values. With Epi treatment, SW was reduced for a given LV end-diastolic volume compared with the control study. Epi treatments also caused relatively higher plasma thromboxane B2 concentrations postshock. CONCLUSION: Our findings indicate that, when given immediately postshock, bolus-Epi did not hasten recovery and caused impairment in LV mechanics in canine AS. (+info)
Inhibitory effects of copper-aspirin complex on platelet aggregation.
(4/1005)
AIM: To study the inhibitory effects of copper-aspirin complex (CuAsp) on platelet aggregation. METHODS: With adenosine diphosphate the effects of CuAsp on platelet aggregation in vitro or in vivo were investigated. Radioimmunoassay and fluorophotometry were used to measure thromboxane B2 (TXB2) generation from platelets, the levels of TXB2 and of 6-keto-PGF1 alpha in plasma and the platelet serotonin release reaction. RESULTS: In vitro, CuAsp inhibited arachidonic acid (AA)-induced aggregation (IC50 = 17 mumol.L-1, 95% confidence limits: 9-33 mumol.L-1), the release of 5-HT (IC50 = 19 mumol.L-1, 95% confidence limits: 10-30 mumol.L-1), and TXB2 generation from platelets (P < 0.05). CuAsp 10 mg.kg-1 i.g. selectively inhibited AA-induced aggregation, and increased the 6-keto-PGF1 alpha concentration in plasma while decreased that of TXB2. CONCLUSION: CuAsp, in vitro or in vivo, shows more potent inhibitory effects on AA-induced aggregation than aspirin (Asp), related to the inhibition of platelet cyclooxygenase and the release of active substances from platelets. (+info)
Mepyramine inhibits platelet activating factor-induced rabbit platelet aggregation: role of intracellular histamine.
(5/1005)
AIM: To study the possible role of intracellular histamine (HA) in platelet activating factor (PAF)-induced platelet activation. METHODS: Washed rabbit platelet suspension was used to test the inhibitory effect of mepyramine (Mep, an H1 receptor antagonist) on PAF-induced platelet aggregation. The thromboxane B2 (TXB2) generation was measured by radioimmunoassay and the intracellular calcium ([Ca2+]i) concentration was determined by the specific fluorescence indicator Fura-2. RESULTS: Mep > 100 mumol.L-1 generated a concentration-dependent inhibition on PAF-induced aggregation, with an IC50 value of 162 (95% confidence limits: 114-232 mumol.L-1). Cimetidine, an H2 receptor antagonist, even up to 400 mumol.L-1 had no effect on it. Exogenous HA (10 mumol.L-1) and H1 receptor agonist, 2-thiazolylethylamine had no energetic effect. alpha-Fluoromethylhistidine, an inhibitor of histidine decarboxylase, did not inhibit platelet responses. However, in platelets permeabilized with saponin (8-10 mg.L-1), exogenous HA attenuated the inhibitory effect of Mep to about 50% at a concentration of 50 mumol.L-1. Preincubation of platelets with Mep (100 or 200 mumol.L-1) resulted in an inhibition on TXB2 generation and [Ca2+]i elevation induced by PAF. CONCLUSION: Platelets activated by PAF is associated with an intracellular HA synthesis and release via a common pathway of TXB2 generation and the rise of [Ca2+]i. (+info)
Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.
(6/1005)
Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxicity. The present study was undertaken to assess the renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomized under double-blind conditions to receive the specific Cox-2 inhibitor, MK-966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decline in urinary sodium excretion during the first 72 h of treatment. Blood pressure and body weight did not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1alpha was decreased by both MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a role in the systemic biosynthesis of prostacyclin in healthy humans. Selective inhibition of Cox-2 by MK-966 caused a clinically insignificant and transient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline in GFR. Our data suggest that acute sodium retention by nonsteroidal anti-inflammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1. (+info)
In vitro prostanoid release from spinal cord following peripheral inflammation: effects of substance P, NMDA and capsaicin.
(7/1005)
1. Spinal prostanoids are implicated in the development of thermal hyperalgesia after peripheral injury, but the specific prostanoid species that are involved are presently unknown. The current study used an in vitro spinal superfusion model to investigate the effect of substance P (SP), N-methyl-d-aspartate (NMDA), and capsaicin on multiple prostanoid release from dorsal spinal cord of naive rats as well as rats that underwent peripheral injury and inflammation (knee joint kaolin/carrageenan). 2. In naive rat spinal cords, PGE2 and 6-keto-PGF1alpha, but not TxB2, levels were increased after inclusion of SP, NMDA, or capsaicin in the perfusion medium. 3. Basal PGE2 levels from spinal cords of animals that underwent 5-72 h of peripheral inflammation were elevated relative to age-matched naive cohorts. The time course of this increase in basal PGE2 levels coincided with peripheral inflammation, as assessed by knee joint circumference. Basal 6-keto-PGF1alpha levels were not elevated after injury. 4. From this inflammation-evoked increase in basal PGE2 levels, SP and capsaicin significantly increased spinal PGE2 release in a dose-dependent fashion. Capsaicin-evoked increases were blocked dose-dependently by inclusion of S(+) ibuprofen in the capsaicin-containing perfusate. 5. These data suggest a role for spinal PGE2 and NK-1 receptor activation in the development of hyperalgesia after injury and demonstrate that this relationship is upregulated in response to peripheral tissue injury and inflammation. (+info)
Effects of leukocyte-depleted warm blood cardioplegia on cardiac and endothelial function.
(8/1005)
It has been reported that neutrophils and platelets have deleterious effects on myocardium and endothelium during and after ischemia. In this study we evaluated the effects of a leukocyte-depleting filter (Sepacell PLX, Asahi medical, Tokyo) during warm blood cardioplegia and early reperfusion on cardiac and endothelial function in the blood-perfused rat heart. Hearts (n = 7 per group) from donor rats were excised and perfused with blood at 37 degrees C from a support rat. After 10 min of stabilization, the hearts were arrested for 60 min with warm blood cardioplegia given at 20 min intervals. This was followed by 60 min of reperfusion. A leukocyte-depleting filter was used during the cardioplegia and the initial 10 min of reperfusion in the experimental group (Group F) and it was not used in the control group (Group N). Left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximum rate of left ventricular pressure rise (+dp/dt) and maximum rate of left ventricular pressure fall (-dp/dt) were measured as indices of left ventricular function before and after cardioplegic arrest. Coronary sinus effluent was obtained and the levels of MB isozyme of creatine kinase (CKMB), malondialdehide (MDA), elastase and thromboxane B2 (TXB2) were measured as indices of myocardial and endothelial injury. After 60 min of reperfusion, acetylcholine (Ach.) was administered to the coronary perfusate and the difference of nitric oxide (NO) concentration between inflow and outflow, and coronary blood flow were measured as an indication of endothelial function. Group F showed significantly lower LVEDP than Group N at 10 min of reperfusion. The elastase levels were significantly (p < 0.05) lower and the CKMB levels tended (p < 0.1) to be lower in Group F at 60 min of reperfusion. The administration of Ach. to the coronary perfusate showed significantly (p < 0.05) greater coronary blood flow and NO production in Group F. The results suggested that the use of a leukocyte-depleting filter during warm blood cardioplegia and early reperfusion preserves endothelial function and left ventricular diastolic compliance. The technique may provide beneficial effects by reducing reperfusion injury in patients undergoing cardiac surgery. (+info)