Elevated platelet count, C-reactive protein and thromboxane analog-induced platelet aggregation in patients with Gulf War veterans' illnesses: evidence of a chronic inflammatory state?

A previous study of Gulf War veteran's illnesses (GWVI) observed evidence of platelet activation in a majority of patients with GWVI. To further characterize platelet function, we studied 43 patients (40 men) with GWVI (GWVI+) and 21 veterans who served concurrently in the Gulf War but who lacked criteria for GWVI (GWVI-). All participants were free of infection and known inflammatory diseases. Studies performed included platelet count, immature platelet fraction (IPF), plasma thrombopoietin (TPO), C-reactive protein (CRP), platelet aggregation and ATP secretion in response to six agonists, and spontaneous aggregation. Platelet counts and CRP were significantly elevated in GWVI+ compared to GWVI- patients without elevation in IPF or TPO. Platelet aggregation did not differ between GWVI+ and GWVI- patients except for spontaneous aggregation that was significantly greater in GWVI+ patients. Platelet ATP secretion was similar in the two groups, except the response to 50 µmol/l thrombin receptor agonist peptide 6 (TRAP 6) was significantly greater in GWVI+ patients. When platelet aggregation was analyzed in relation to CRP, the response to 0.5 µmol/l U46619 was significantly greater in patients whose CRP was at least 2 µg/ml. Therefore, GWVI+ patients had elevated platelet counts, spontaneous aggregation, TRAP 6-induced secretion, and CRP, but no impairment of platelet function. The increased platelet counts and U46619-induced aggregation appear to be consequences of an underlying inflammatory state in GWVI.

Effects of centrally administered prostaglandin E(3) and thromboxane A(3) on plasma noradrenaline and adrenaline in rats: comparison with prostaglandin E(2) and thromboxane A(2).

Previously, we reported the involvement of brain omega-6 prostanoids, especially prostaglandin E(2) and thromboxane A(2), in the activation of central sympatho-adrenomedullary outflow in rats. omega-3 Prostanoids, including prostaglandin E(3) and thromboxane A(3), are believed to be less bioactive than omega-6 prostanoids, although studies on the functions of omega-3 prostanoids in the central nervous system have not been reported. In the present study, therefore, we compared the effects of centrally administered omega-3 prostanoids, prostaglandin E(3) and thromboxane A(3), with those of omega-6 prostanoids, prostaglandin E(2) and thromboxane A(2), on the plasma catecholamines in anesthetized rats. Intracerebroventricularly (i.c.v.) administered prostaglandin E(2) (0.15, 0.3 and 1.5 nmol/animal) and prostaglandin E(3) (0.3 and 3 nmol/animal) predominantly elevated plasma noradrenaline but not adrenaline, but the latter was less efficient than the former. On the other hand, U-46619 (an analog of thromboxane A(2)) (30, 100 and 300 nmol/animal, i.c.v.) and Delta(17)-U-46619 (an analog of thromboxane A(3)) (100 and 300 nmol/animal, i.c.v.) both elevated plasma catecholamines (adrenaline>>noradrenaline) to the same degree. These results suggest that centrally administered prostaglandin E(3) is less effective than prostaglandin E(2) to elevate plasma noradrenaline, and that thromboxane A(3) is almost as equipotent as thromboxane A(2) to elevate plasma catecholamines in rats.

Estudo da reposição volêmica inicial em modelo experimental de choque hemorrágico associado ao traumatismo craniencefálico: comparação entre as soluções de ringer lactato e salina hipertônica 3 por cento / Volume replacement with lactated ringer's or 3 per cent hypertonic saline solution during combined experimental hemorrhagic shok and traumatic brain injury

Este estudo avalia a resposta hemodinâmica sistêmica e cerebral à reposição volêmica com Solução de Ringer Lactato (RL) ou Salina Hipertônica a 3 por cento (SSH 3 por cento) e o comportamento da liberação de prostanóides encefálicos durante a fase aguda do choque hemorrágico (CH) associado ao traumatismo craniencefálico (TCE). Quinze cães foram distribuidos em três grupos (RL, SSH3 por cento, controle) e após CH eTCE simulamos o tratamento durante a fase pré-hospitalar e hospitalar precoce. No evento de um trauma de crânio grave e choque hemorrágico, o uso de SSH 3 por cento ou o dobro do volume de RL promoveram benefícios hemodinâmicos sistêmicos e cerebrais semelhantes. Os valores mais baixos de PIC foram observados após SSH 3 por cento. Não houve diferença nos valores da concentração venosa cerebral de prostaglandina e tromboxane.

This study evaluates the systemic and cerebral hemodynamic responses to volume replacement with 3 per cent hypertonic saline (HSS) or lactated Ringer’s solution (LR), during the acute phase of hemorrhagic shock (HS) associated with traumatic brain injury (TBI). Fifteen mongrel dogs were assigned to one of three groups (LR, HSS, control) and after HS+TBI we simulated treatment during prehospital and early hospital admission. In the event of severe head trauma and hemorrhagic shock, the use of HSS and larger volumes of LR promote similar systemic and cerebral hemodynamic benefits. A lower ICP was observed after HSS 3 per cent than after LR. There were no differences between groups in cerebral venous concentration of tromboxane and prostaglandin.

Pharmacology of airways and vessels in lung slices in situ: role of endogenous dilator hormones.

Small airway and vessels play a critical role in chronic airway and pulmonary vascular diseases, but their pharmacology has not been well characterised. We have studied airway and vascular responses in rat lung slices and separately in vitro using myography. In lung slices, under basal conditions, acetylcholine contracted airways, but had no vascular effect. The thromboxane mimetic, U46619 contracted both vessels and airways. In the presence of U46619, acetylcholine dilated vessels, but further contracted airways, an effect that was blocked by the nitric oxide synthase inhibitor L-NG-nitro-L-arginine or apamin plus charybdotoxin, which inhibit endothelial-derived hyperpolarising factor. Airway responses in lung slices were unaffected by L-NGnitro-L-arginine methyl ester, indomethacin or apamin plus charybdotoxin. By contrast, apamin plus charybdotoxin contracted bronchi studied in isolation. Our observations are the first to identify mechanisms of endothelium dependent dilations in precision cut lung slices and the potential for transverse hormonal communication between airways and vessels.

[Tolerance of moderate hypothermic therapy: it's effect on the neonatal cardiovascular system and particularly pulmonary and intestinal circulation]. / Tolérance de l'hypothermie thérapeutique modérée: son effet sur le système cardiovasculaire néonatal et notamment la circulation pulmonaire et intestinale.

We present a study in which we investigated the safety of therapeutic mild hypothermia on the neonatal cardiovascular system. In an attempt to mimic the state of affairs that may follow an hypoxic-ischemic insult, the effect of moderate hypothermia was studied under conditions where cardiovascular integrity was impaired. Newborn piglets where randomized to either receive a thromboxane A2 mimetic or an hypoxic inspiratory gas mixture. Periods of hypothermia (5 degrees C below normothermic level) preceded or were combined with those agents in a random manner. Isolated hypothermia decreased cardiac output by 25%, and increased pulmonary vascular resistance by 48%. Mesenteric blood flow and cerebral blood flow decreased by a similar magnitude (21 and 18% respectively). When hypothermia was combined with alveolar hypoxia or thromboxane, the increase in pulmonary vascular resistance (103 and 292% respectively) exceeded the increase produced by the sum of each individual component. In contrast neither hypoxia nor thromboxane potentiates the hypothermia induced decrease in mesenteric blood flow. Ileal mucosal blood flow remained stable for all conditions. We conclude that mild therapeutic hypothermia may be safe in conditions where cardiac function is impaired, but may be more hazardous when severe pulmonary hypertension is present.

Papel del factor de activación plaquetaria, los eicosanoides y la bradicinina en la terapia adyuvante de la sepsis / Role of platelet-activating factor, eicosanoids and bradykinin in adjuvant therapy for sepsis

Con el término autocoide se define un grupo de pequeñas moléculas liberadas por diversos tipos celulares y que actúan como hormonass autocrinas y paracrinas. La mayoría de estas moléculas se liberan como parte de la respuesta inflamatoria y están implicadas en la patogénesis de la sepsis y el choque séptico. Entre los autocoides se encuentran los eicosanoides, el factor de activación plaquetaria (PAF) y los mediadores peptídicos bradicinina y calidina. En numerosos modelos animales la administración de fármacos que bloquean la síntesis o los receptores de los autocoides ha mejorado las condiciones de sepsis o shock séptico; no obstante, los resultados son contradictorios cuando se habla de ensayos clínicos (AU)

Inhaled sodium nitroprusside. Non-selective reduction of thromboxane analogue-induced pulmonary vasoconstriction in healthy sheep.

Both inhaled nitric oxide (NO) and inhaled prostacyclin have been shown to selectively decrease pulmonary hypertension of various origin. The aim of the present study was to assess the potential of the NO donor sodium nitroprusside (SNP) to elicit selective pulmonary vasodilation. SNP spontaneously liberates nitric oxide in the presence of reducing substances like cysteine or glutathione, ubiquitous in many different tissues. Inhaled as an aerosol in 3 healthy lambs presenting pulmonary hypertension induced by infusion of a thromboxane analogue, low concentrations of SNP (0.02-0.6 mg/ml) revealed no effect at all. In contrast, high concentrations of SNP (1.0-20.0 mg/ml) lowered pulmonary artery pressure in conjunction with systemic arterial hypotension, suggesting systemic resorption of SNP with subsequent release of its nitroso-group. Selective pulmonary vasodilation was never observed. In conclusion, the present results do not support a selective effect of inhaled SNP in the pulmonary circulation.

Hemodynamic and tubular effects of endothelin and thromboxane in the isolated perfused rat kidney.

We have investigated the effects of the endothelium-derived peptide, endothelin, and of a chemically stable analog of thromboxane (TX) A2, U46619, on the glomerular hemodynamics and tubular function of isolated, perfused rat kidneys. Endothelin (10(-11)-10(-9) M) dose dependently decreased the renal plasma flow to a significantly greater extent than it did the glomerular filtration rate. In contrast, U46619 (10(-9)-10(-7) M) had more pronounced effects on the glomerular filtration rate than on the renal plasma flow. As a consequence, the filtration fraction was increased by endothelin and decreased by U46619. Endothelin, unlike U46619, enhanced urinary Na+ excretion and reduced oxygen consumption at concentrations that greatly decreased the tubular load, thus suggesting that it has a direct effect on tubular Na+ reabsorption. Addition of the TXA2/PGH2-receptor antagonist, BM13177 (4.10(-4) M), or the cyclooxygenase inhibitor, acetylsalicylic acid (10(-3) M), to the perfusion medium failed to modify the endothelin-induced increase in Na+ excretion or the reduction in renal plasma flow, whereas acetylsalicylic acid, but not BM13177, partially prevented the decrease in the glomerular filtration rate. These results demonstrate that two contractile agonists produced by the kidney have specific and differential effects on cortical and tubular functions. Moreover, the intrarenal production of eicosanoids does not appear to play a major role in the renal effects of endothelin.

Effects of administered thromboxanes on the intact, normal rat kidney.

The effects of administered thromboxanes on the intact, normal rat kidney were studied. Euvolemic male rats received intraarterial infusions of thromboxane B2 (TXB2) and the stable thromboxane A2 analog (U46619) and the effects on renal function were investigated, using glomerular micropuncture and whole-kidney clearance techniques. Both TXB2 and U46619 were renal vasoconstrictors and lowered GFR by reducing renal plasma flow rate; U46619 was much more potent that TXB2. Neither agent caused any marked change in the glomerular capillary ultrafiltration coefficient (Kf). Thus in the rat, the thromboxanes reduce filtration rate by increasing renal vascular resistance and without exerting a marked influence on Kf.