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Thromboxane A[sub2] is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in pro-inflammatory reactions. The effects of a novel dual TXA[sub2] synthase inhibitor and TXa[sub2] receptor antagonist [(BM-573) on pulmonary hemodynamics were investigated in endotoxic shock, 30 mins before the start of a 0.5 mg/kg endotoxin infusion, 6 pigs (Endo group) received a placebo infusion and 6 other pigs (Anta group) received a BM-573 infusion. In Endo group, pulmonary artery pressure increased from 25 ± 1.8 (T0) to 42 ± 2.3 mmHg (T60) (p < 0.05) after endotoxin infusion while, in Anta group, it increased from 23 ± 1.6 (T0) to 25 ± 1.5 mmHg (T60). This difference is due to a reduction in pulmonary vascular resistance in Anta group while pulmonary arterial compliance changes in Endo group remained comparable with the evolution in Anta group. In Endo group, PaO[sub2] decreased from 131 ± 21 (T0) to 74 ± 12 mmHg (T300) (p < 0.05), while in Anta group, PaO[sub2] was 241 ± 31 mmHg at the end of the experimental period (T300). These results demonstrate that TXA[sub2] plays a major role in pulmonary vascular changes during endotoxin insult. Concomitant inhibition of TXA[sub2] synthesis and of TXA[sub2] receptors by BM-573 inhibited the pulmonary vasopressive response during the early phase of endotoxin shock as well as the deterioration in arterial oxygenation. [ABSTRACT FROM AUTHOR]

We studied the effects on pulmonary hemodynamics of U-46619, a thromboxane A[sub2] (TXA[sub2]), agonist, before and after administration of a novel TXA[sub2] receptor antagonist and synthase inhibitor (BM-573). Six anesthetized pigs (Ago group) received 6 consecutive injections of U-46619 at 30-min interval and were compared with six anesthetized pigs (Anta group) which received an increasing dosage regimen of BM-573 10 min before each U-46619 injection. Consecutive changes in pulmonary hemodynamics, including characteristic resistance, vascular compliance, and peripheral vascular resistance, were continuously assessed during the experimental protocol using a four-element Windkessel model. At 2 mg/kg, BM-573 completely blocked pulmonary hypertensive effects of U-46619 but pulmonary vascular compliance still decreased. This residual effect can probably be explained by a persistent increase in the tonus of the pulmonary vascular wall smooth muscles sufficient to decrease vascular compliance but not vessel lumen diameter. Such molecule could be a promising therapeutic approach in TXA[sub2] mediated pulmonary hypertension as it is the case in pulmonary embolism, hyperacute lung rejection and endotoxinic shock. [ABSTRACT FROM AUTHOR]

Lumped models are frequently used to provide a satisfactory descriptionof the hemodynamic properties of the pulmonary vasculature. The purpose ofthis study is to describe a method to identify simultaneously the parametersvalues of windkessel models components. The following equation was used toobtain R[sub 1] (characteristic resistance), R[sub 2] (peripheralresistance), C (total compliance) and L (inertance): For formulae see full text. where k[sub i] are the following functions of L, R[sub 1] , R[sub 2] and C: For formulae see full text. To assess the accuracy of the method, estimates of R[sub 1] , R[sub 2] , and C were compared to characteristic impedance R[sub c] , vascularresistance PVR and pulmonary arterial compliance C[sub d] respectivelycomputed from referenced methods. Comparison between R[sub 1] and R[sub c] , PVR and R[sub 1] + R[sub 2] , C and C[sub d] were obtainedin 5 anaesthetised pigs during basal conditions and after endotoxin-shock. The results indicate that in both conditions, comparisons evidenced highlysignificant correlations between values computed by the different approaches(p < 0.0001). Although our method yielded to consistently lower valuesthan values provided by referenced methods, the results were concordant withrespect to the expected response of pulmonary vasculature to endotoxin insult.We conclude that our method of identification is suitable for the assessmentof lumped parameters windkessel model estimates. The main interest is thatactual resistance and compliance values can be obtained easily and simultaneouslyby a global method approach. [ABSTRACT FROM AUTHOR]