sq-29548 and Streptococcal-Infections

Group B Streptococcus (GBS) causes an impairment of diaphragmatic pressure generation (Pdi) in 2-wk-old piglets, whereas 4-wk-old piglets are unaffected. In this study, we examined the effect on 4-wk-old piglets of a higher dose of GBS than previously utilized. We sought to determine whether an eicosanoid product of arachidonic acid metabolism accounted for the decrease in Pdi during GBS infusion and whether thromboxane A2 (TxA2) is the putative eicosanoid mediator of decreased Pdi during GBS infusion. Measuring Pdi during phrenic nerve stimulation, we studied four groups of anesthetized spontaneously breathing 4-wk-old piglets. Group 1 (GBS) was infused with live GBS, which caused a decrease in Pdi by 1 h at 20-, 30-, 50-, and 100-Hz stimulation frequencies. Group 2 [GBS + indomethacin (Indo)] was pretreated with Indo before GBS infusion. In the GBS + Indo group, Pdi did not decrease throughout 4 h of GBS infusion. Because Indo proved to be protective of Pdi during GBS infusion, we examined the role of TxA2, the only eicosanoid present at 1 h in the serum of GBS-infused piglets. Group 3 was infused with the TxA2 analogue U-46619 only for 1 h. Group 4 was treated with the TxA2-receptor antagonist SQ-29548 before and concomitant with GBS infusion for 1 h; the SQ-29548 was then discontinued, and GBS was continued for 1 h more. In the U-46619-infused group, Pdi decreased at 1 h, and in the SQ-29548-treated group, Pdi did not decrease during GBS infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Gas Analysis; Bridged Bicyclo Compounds, Heterocyclic; Diaphragm; Electric Stimulation; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Indomethacin; Muscle Contraction; Pressure; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Receptors, Thromboxane; Regional Blood Flow; Respiratory Mechanics; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane A2; Vasoconstrictor Agents

Early-onset neonatal group B beta-hemolytic streptococcus (GBS) infection exhibits pathophysiologic characteristics of a toxic shock syndrome, in which a cascade of inflammatory mediators are involved. Thromboxane A2 (TXA2) is thought to play an important role as a mediator of the pulmonary response to GBS toxin, because high lung lymph concentrations of a TXA2 metabolite have been observed after GBS toxin injections in sheep. The aim of this study was to evaluate the effects of a selective antagonist of the TXA2-prostaglandin endoperoxide receptor (SQ 29,548). Six unanesthetized young lambs, each serving as its own control, were given SQ 29,548 or vehicle control followed by GBS toxin challenge. Hemodynamic and lung function (lung mechanics, lung volume, ventilation) responses were followed for 5 h. When compared with the control studies, treatment with SQ 29,548 significantly altered the response to GBS toxin. SQ 29,548 reduced the increase in pulmonary and systemic vascular resistance, improved cardiac output and stroke volume, improved dynamic lung compliance but not airway resistance, and improved oxygenation. The attenuating effect of SQ 29,548 was most pronounced during the first phase of toxin response (15-90 min after toxin infusion), but significant treatment effects were also seen during the second phase (120-300 min after toxin infusion). This study demonstrates that TXA2 is an important mediator of the response to GBS toxin and is responsible for hemodynamic and lung function changes. Thromboxane receptor blockade may offer a potential therapeutic approach to infants with severe early-onset GBS sepsis.

Topics: Airway Resistance; Animals; Bacterial Toxins; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Output; Disease Models, Animal; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Lung; Pulmonary Gas Exchange; Receptors, Thromboxane; Respiratory Mechanics; Sheep; Streptococcal Infections; Streptococcus agalactiae; Stroke Volume; Thromboxane A2; Vascular Resistance