Effect of phospholipase C blockade on cerebral vasospasm.

BACKGROUND: Delayed cerebral ischemia due to cerebral vasospasm remains a major cause of morbidity and mortality following subarachnoid hemorrhage. Oxyhemoglobin (OxyHb) and vasoconstrictor prostanoids have been suggested as putative spasmogens. We have previously reported a synergistic vasoconstrictive action between thromboxane A(2) (TXA(2)) and OxyHb. In the present study we examine the effect of neomycin, a phospholipase C inhibitor, on the cerebral vasoconstriction induced by TXA(2) and OxyHb. METHODS: Using an in vitro tissue bath method, we assess the effect of neomycin in a concentration-dependent manner, on isolated porcine basilar arteries constricted by U-46619 (TXA(2) analogue) and OxyHb. RESULTS: The functional synergism between TXA(2) and OxyHb, leading to significant cerebral vasoconstriction, is attenuated in a dose-dependent manner by neomycin. CONCLUSION: Blockade of phospholipase C may provide an alternative strategy in the treatment of subarachnoid-hemorrhage-induced cerebral vasospasm.

Pathogenic role of thromboxane A2 in immediate food hypersensitivity reactions in children.

BACKGROUND: Food hypersensitivity, from the standpoint of pathogenesis as well as clinical management, remains controversial. During the food allergen-induced immediate hypersensitivity reaction, various chemical mediators are released. OBJECTIVE: The purpose of our study was to determine whether thromboxane A2 participates in food antigen-induced responses in children with food hypersensitivity. METHODS: Nine open food challenges were performed in nine patients with suspected food hypersensitivity. Plasma thromboxane B2 and histamine levels were measured during a 24-hour period following the challenge. RESULTS: All the patients demonstrated immediate reactions after food challenge. The mean plasma thromboxane B2 level (a marker of thromboxane A2 activity) rose significantly at two hours and three hours after the challenge. Simultaneously, the mean plasma histamine level rose significantly at two hours and three hours after the challenge. CONCLUSIONS: The results suggest that thromboxane A2 may play a pathogenic role in part in the immediate reaction after food challenge and that thromboxane A2 is probably released from a common cellular source (eg, mast cell) with histamine and/or by a common mechanism (eg, IgE-dependent platelet activation).

Papel del tubo digestivo en la generación del síndrome de falla múltiple de órganos / Role of the digestive system in the generation of the multiple organ failure syndrome

El síndrome de falla múltiple de órganos (SFMO) es un problema común en las UTIs. En su generación intervienen múltiples agentes tóxicos. El intestino parece ser una fuente importante de los mismos ya que es particularmente sensible a la isquemia y reperfusión. De hecho el acoplamiento DO2-VO2 se observa antes que en el resto del organismo. Esto lo convierte en un gatillo de lesión a distancia, permitiendo el paso de mediadores a la circulación general con reinicio sistémico del ciclo liberación-lesión

Papel del tubo digestivo en la generación del síndrome de falla múltiple de órganos / Role of the digestive system in the generation of the multiple organ failure syndrome

El síndrome de falla múltiple de órganos (SFMO) es un problema común en las UTIs. En su generación intervienen múltiples agentes tóxicos. El intestino parece ser una fuente importante de los mismos ya que es particularmente sensible a la isquemia y reperfusión. De hecho el acoplamiento DO2-VO2 se observa antes que en el resto del organismo. Esto lo convierte en un gatillo de lesión a distancia, permitiendo el paso de mediadores a la circulación general con reinicio sistémico del ciclo liberación-lesión (AU)

Comparison of antithrombotic effects of GPIIb-IIIa receptor antagonist and TXA2 receptor antagonist in the guinea-pig thrombosis model: possible role of TXA2 in reocclusion after thrombolysis.

The effects of Ro 44-9883, a new specific antagonist of platelet glycoprotein IIb-IIIa receptor, on thrombus formation and reocclusion after thrombolysis induced by tissue-type plasminogen activator (t-PA) were compared with those of vapiprost, a thromboxane (TX) A2 receptor antagonist, using a photochemically-induced thrombosis model in the guinea-pig femoral artery. Pretreatment with Ro 44-9883 (5, 10 and 20 micrograms/kg/min, i.v.) prolonged the time required to occlude the artery in a dose-dependent manner. Ro 44-9883 at 10 and 20 micrograms/kg/min significantly inhibited ex vivo platelet aggregation in whole blood induced by collagen, ADP or U46619. Vapiprost 0.3 mg/kg inhibited thrombus formation and platelet aggregation induced by collagen or U46619, to the same extent as Ro 44-9883 at the higher doses. In the thrombolysis study, Ro 44-9883 at the higher doses given as comedication with t-PA reduced the time to achieve reperfusion and increased the vascular patency after successful reperfusion. Vapiprost also significantly reduced the time to reperfusion and prevented reocclusion. However, the vascular patency after thrombolysis by t-PA with vapiprost was significantly increased compared with Ro 44-9883. Ro 44-9883 inhibited platelet aggregation, but did not prevent TXA2 formation in platelets. Thus, vascular contraction mediated by platelet-derived TXA2 may be responsible for lower efficacy of Ro 44-9883 against reocclusion compared with vapiprost. These results indicate that not only platelet aggregation but also vasoconstriction may contribute to reocclusion after t-PA-induced thrombolysis in the guinea-pig.

[Losartan prevents pulmonary hypertension induced by a thromboxane A2 analog]. / Le losartan prévient l'hypertension pulmonaire induite par un analogue du thromboxane A2.

We investigated the possibility that the selective angiotensin II type 1 (AT1) receptor antagonist, losartan, interacts with thromboxane A2/endoperoxide (TxA2/PGH2) receptors. We measured changes in mean pulmonary arterial pressure (MPAP) induced by the stable TxA2 analogue, U-46619, during blockade of either TxA2/PGH2 or AT1 receptors, in anesthetized, open chest rats (n = 4-8 per group). U-46619 (1.25 and 10 micrograms/kg) dose-dependently increased MPAP. The U-46619 (1.25 micrograms/kg)-evoked increase in MPAP (approximately 51%; p < 0.01) was dose-dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 (approximately 94 and 102% at 0.63 and 2.5 mg/kg, respectively; both p < 0.05). Losartan also dose-dependently reduced this increase (approximately 11 and 65% at 2.5 and 10 mg/kg, respectively; p = NS and p < 0.05, respectively). Furthermore, losartan dose-dependently prevented the increase in MPAP (approximately 112%) induced by an 8 fold higher dose of U-46619 (10 micrograms/kg) by approximately 9 and 75% at doses of 10 and 40 mg/kg, respectively; p = NS and p < 0.05, respectively. Thus, selective activation of TxA2/PGH2 receptors by the TxA2 analogue, U-46619, induced pulmonary hypertension, which was specifically inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 and the AT1 receptor antagonist, losartan, suggesting that the latter compound exerts antagonist activity at TxA2/PGH2 receptors.