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We studied the effects of LY-163443, a novel selective receptor antagonist of LTD4 and LTE4, in splanchic artery occlusion (SAO) shock. LY-163443 antagonized the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats. Anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 minutes developed a severe shock state usually resulting in a fatal outcome within two hours after release of the occlusion. SAO shock rats pre-treated with LY-163443 before the occlusion of the splanchnic arteries maintained post-release MABP at significantly higher values compared to rats receiving either the vehicle or LY-163443 as a post-treatment 15 min after occlusion (final MABP 96 +/- 8 vs 51 +/- 1, p less than 0.01 and 53 +/- 3, p less than 0.01, respectively). Pre-treatment with LY-163443 attenuated the release of the lysosomal hydrolase, cathepsin D (p less than 0.01 from vehicle and p less than 0.05 from post-treatment groups), and the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in the pre-treatment group than in the vehicle group (27 +/- 3 vs 51 +/- 6 U/ml, p less than 0.01). SAO shock rats pretreated with LY-163443 also exhibited significantly higher survival rates (p less than 0.01 from vehicle and post-treatment groups), and prolonged survival times (p less than 0.01 from vehicle and post-treatment groups).(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using WEB 2086, a specific antagonist of PAF. WEB 2086 (0.5 mg/kg) significantly reversed the decrease in mean arterial blood pressure (MABP) induced by PAF (0.3 micrograms/kg) in anesthetized rats. Anesthetized rats were subjected to Noble-Collip drum trauma. Traumatized rats treated with WEB 2086 (0.5 mg/kg bolus followed by infusion at 0.5 mg/kg/hr) maintained a higher MABP than those receiving only the vehicle (0.9% NaCl). Improvement in MABP paralleled a significant increase in overall survival time (p less than 0.01) in rats receiving WEB 2086 (0.5 mg/kg). WEB 2086 also significantly attenuated the plasma accumulation of the lysosomal hydrolase, cathepsin D and of free amino-nitrogen compounds, compared to shocked rats receiving only the vehicle. Furthermore, the production of the cardiotoxic peptide, myocardial depressant factor (MDF) was also blunted by WEB 2086. These results suggest that PAF may be an important mediator in the pathogenesis of traumatic shock in rats. Furthermore, PAF receptor antagonists may be useful as therapeutic agents when given early in the course of ischemic and shock states.

The peptide leukotrienes are biologically active eicosanoids which have recently been implicated as possible mediators of anaphylactic, endotoxic, traumatic, and splanchnic artery occlusion shock. We studied the effects of a novel selective peptide leukotriene antagonist, L-649,923, in a rat model of hemorrhagic shock. Hemorrhaged rats treated with L-649,923 (1 mg/kg/h) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg/h) of L-649,923 (final MABP 97 +/- 4 vs 60 +/- 5, p less than 0.01; vs 60 +/- 4 mm Hg, p less than 0.01, respectively). Both doses of L-649,923 attenuated the increase in plasma cathepsin D activity (p less than 0.01). L-649,923, at 1 mg/kg/h, also attenuated the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with L-649,923 (1 mg/kg/h) than in rats receiving the lower dose of the drug or the vehicle (36 +/- 5 U/ml vs. 61 +/- 4 U/ml, p less than 0.01; and 60 +/- 3 U/ml, p less than 0.01, respectively). Furthermore, L-649,923 does not inhibit platelet aggregation in platelet rich plasma. Our data suggest that peptide leukotrienes are important mediators of hemorrhagic shock and that blockade of leukotriene-induced vasoconstriction may underlie the beneficial effects of L-649,923 in hemorrhagic shock.

The effect of 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone (pimobendan, UD-CG 115 BS), a novel positive inotropic and vasodilator agent, was studied in a severe model of murine traumatic shock. Noble-Collip drum trauma produced a shock state characterized by a significantly reduced mean arterial blood pressure (MABP), a 5-fold increase in plasma cathepsin D and myocardial depressant factor (MDF) activities, and a survival time of 80 +/- 12 min. Administration of pimobendan (100 micrograms/kg, i.v. bolus) significantly prolonged the survival time to 175 +/- 24 min (p less than 0.01). Although plasma cathepsin D was not affected by pimobendan, this agent significantly attenuated the accumulation of MDF activity in the plasma when compared to animals receiving only its vehicle (37 +/- 6 vs 61 +/- 9 U/ml, p less than 0.05). Additionally, pimobendan inhibited platelet aggregation in cat platelet rich plasma, but failed to have an antiproteolytic effect in cat pancreatic homogenates. These results suggest that cardiotonic and vasodilator activities combined with inhibition of platelet aggregation could mediate the beneficial effects of pimobendan in traumatic shock.

We studied the effects of a potent, specific platelet activating factor (PAF) antagonist, CV-6209, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CV-6209 (1 mg/kg) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg) of CV-6209 (final MABP 88 +/- 4 vs. 57 +/- 4, vs. 61 +/- 7 mm Hg, respectively). CV-6209 (1 mg/kg) also significantly attenuated the increase in plasma cathepsin D activity following hemorrhage compared with hemorrhaged rats receiving only its vehicle (i.e. 0.9% NaCl). CV-6209 (1 mg/kg) also significantly decreased the plasma accumulation of free amino-nitrogen compounds and the plasma activity of a myocardial depressant factor (MDF) compared to hemorrhaged rats receiving 0.9% NaCl. Rats receiving CV-6209 (1 mg/kg) exhibited a significantly increased survival rate and survival time post-reinfusion compared to rats receiving only the vehicle. These data indicate that PAF is an important mediator of hemorrhagic shock in the rat and that PAF receptor antagonists may be useful in hemorrhagic shock states.

We studied the effects of prostaglandin E1 (PGE1) in a severe model of hemorrhagic shock in rats. PGE1 was administered as a continuous IV infusion of either 0.1 microgram/kg/min or 1.0 microgram/kg/min starting 30 minutes after the onset of bleeding and continuing until one hour after reinfusion. Hemorrhaged rats treated with PGE1 (1 microgram/kg/min) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (ie, 0.9% NaCl) (final MABP 84 +/- 3 vs 57 +/- 4 mm Hg, P less than .01). PGE1 at 1 microgram/kg/min also attenuated the increase in plasma activities of cathepsin D (P less than .01), and at both doses blunted the plasma accumulation of free amino-nitrogen compounds (P less than .02 at 0.1 microgram/kg/min and P less than .01 at 1.0 microgram/kg/min). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with PGE1 (1 microgram/kg/min) than in rats receiving the vehicle (35 +/- 4 U/mL vs 74 +/- 12 U/mL, P less than .01). Rats receiving PGE1 (1.0 microgram/kg/min) also exhibited a significantly increased survival rate (P less than .01) and post-reinfusion survival time (P less than .01) compared with rats receiving only the vehicle. Our data suggest that antiproteolytic and membrane-stabilizing actions of PGE1 are important and may contribute to its beneficial effects in hemorrhagic shock. Other mechanisms (eg, inhibition of platelet aggregation and vasodilation) may also be involved.

We studied RO 15-1788, a new benzodiazepine receptor antagonist, [ethyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo (1, 5a) (1, 4) benzodiazepine-3-carboxylate] to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with RO 15-1788 maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving only the vehicle (final MABP 114 +/- 4 vs 82 +/- 4 mmHg, p less than 0.001). Moreover, RO 15-1788 decreased the release of the lysosomal hydrolase, cathepsin D (p less than 0.02) into the circulation and blunted the plasma accumulation of free amino-nitrogen groups (p less than 0.01). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in RO 15-1788 treated rats subjected to hemorrhagic shock than in those given the vehicle (18 +/- 2 vs 42 +/- 4 U/ml, p less than 0.01). Additionally, in vitro analysis indicated that RO 15-1788 antagonizes PAF induced coronary vasoconstriction and cardiac depression observed in perfused rat hearts, as well as inhibiting PAF induced platelet aggregation in cat platelet rich plasma. Our results suggest that antagonism of PAF actions can contribute significantly to the beneficial effects of RO 15-1788 in hemorrhagic shock.

We studied the effects of human superoxide dismutase (h-SOD) in splanchnic artery occlusion (SAO) shock. Pentobarbital anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state usually resulting in a fatal outcome within 20 min after the release of the occlusion. h-SOD (10 mg/kg) was infused intravenously starting at reperfusion and lasting for 10 min. SAO shock rats treated with h-SOD maintained postreperfusion MABP at significantly higher values compared to rats receiving the vehicle (final MABP 84 +/- 6 vs 46 +/- 1 mm Hg, P less than 0.01, respectively). Treatment with h-SOD attenuated the plasma accumulation of free amino-nitrogen compounds (P less than 0.01 from vehicle) as well as the activity of the lysosomal protease cathepsin D (P less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in h-SOD-treated rats than in SAO rats receiving only the vehicle (27 +/- 1 vs 64 +/- 3 U/ml, P less than 0.01). SAO shock rats treated with h-SOD also exhibited a significantly higher survival rate than the SAO shock +/- vehicle group (88% vs 11%, P less than 0.01, respectively). These results support the role of oxygen-derived radicals in the pathophysiology of SAO shock, and indicate that h-SOD effectively ameliorates the deleterious effects of oxygen radicals in this severe model of ischemia and reperfusion.

Hypertonic saline (ie, 7.5% NaCl) was injected intravenously (4 ml/kg bolus) to determine its effects in feline and murine models of hemorrhagic shock. Hypertonic NaCl transiently improved mean arterial blood pressure (MABP), superior mesenteric artery blood flow (SMAF), and cardiac output (CO) during the oligemic period. These effects lasted from 15 to 75 min. However, after reinfusion of blood, shocked cats which received 7.5% NaCl during the oligemic period, maintained MABP, SMAF, and CO at significantly higher values compared to cats receiving 0.9% NaCl. The postreinfusion values of these hemodynamic variables in cats given hypertonic NaCl were not statistically different from those of sham-shock cats. Hypertonic NaCl did not attentuate the increase in plasma cathepsin D activity or plasma proteolysis in either cats or rats. Nevertheless, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in shock cats and rats given hypertonic saline compared with the 0.9% NaCl groups (31 +/- 4 vs 54 +/- 7 U/ml, p less than 0.02, in cats; and 27 +/- 2 vs 51 +/- 7 U/ml, p less than 0.02, in rats). The beneficial effects of small-volume resuscitation with 7.5% NaCl during hemorrhagic shock in cats and rats are likely due to the transient hemodynamic improvement during the oligemic period rather than sustained improvement in splanchnic perfusion or in prevention of cellular injury during shock. Our results in two species (eg, cat and rat) suggest that small-volume resuscitation with 7.5% NaCl may be a useful initial treatment of hemorrhagic shock when supplemented by subsequent blood transfusion or perhaps some other appropriate pharmacologic intervention.

It was reported recently that adequate gas exchange could be maintained in patients and experimental animals by applying very high-frequency (15 Hz), low-volume oscillations at the upper airways. This report deals with a new mode of high-frequency ventilation, in which gas exchange is achieved in paralyzed cats by externally vibrating the chest wall. These vibrations, which alone caused very small-volume (less than 0.5 ml) oscillations at the tracheal opening, maintained gas exchange at normal PaCO2 for hours when coupled with tracheal air insufflation. PaCO2 values as low as 15 torr could be achieved by increasing the insufflation rate. Vibration frequencies in the range of 20-45 Hz were equally effective. The method required little or no continuous positive airway pressure, caused little elevation of mean tracheal pressure, and no consistent changes in arterial and central venous pressures during ventilation. In addition to the potential merits of this method of ventilation, the described vibrations seem to considerably reduce the anatomic dead space and as such may assist conventional methods of artificial ventilation or even spontaneous breathing when rapid and shallow.