Beneficial effects of a 5-lipoxygenase inhibitor in endotoxic shock in the rat

The effects of a highly selective 5-lipoxygenase inhibitor, CGS8515 {methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino]benzoate}, on endotoxic shock sequelae and eicosanoid synthesis by peritoneal macrophages were evaluated in the rat. Pretreatment of peritoneal macrophages in vitro with CGS8515 significantly inhibited the synthesis (P < .01) of immunoreactive leukotriene C₄/leukotriene D₄ stimulated by the calcium ionophore (A23187). Inhibition of 5-lipoxygenase produced significant shunting to immunoreactive thromboxane B₂ formation (P < .05). In rats sedated with ketamine·HCl (82.5 mg/kg) and xylazine·HCl (27.5 mg/kg), i.v. injection of Salmonella enteritidis endotoxin (25 mg/kg i.v.) produced significant decreases at 30 min in mean arterial pressure (from 89 ± 4 to 44 ± 8 mm Hg, N = 5, P < .001); in white blood cell count (from 10.8 ± 0.6 to 6.5 ± 0.8 x 10³/mm³, N = 5, P < .01); in platelet count (from 687 ± 66 to 392 ± 65 x 10³/mm³, N = 5, P < .01); and produced an increase of hematocrit (from 46 ± 1.2 to 57.4 ± 1.8%, N = 5; P < .03). CGS8515 (5 mg/kg i.v. 30 min before endotoxin injection, N = 6) blunted the endotoxin-induced hypotension by 35% (P < .001), the leukopenia by 24% ( P < .03), the thrombocytopenia by 45% (P < .006) and the hemoconcentration by 16% (P < .03), compared to the shocked control rats 30 min after endotoxin injection. In subsequent studies, rats were pretreated with CGS8515 (30 mg/kg i.v. 30 min before endotoxin) and sacrificed 4 hr after endotoxin injection. CGS8515 significantly reduced (P < .01) the increase in hematocrit from 56.5 ± 1.4% (N = 6) to 46.6 ± 0.5% (N = 5) compared to shocked controls. CGS8515 also significantly blunted (P < .03) the hypoglycemia from 62.0 ± 7 mg/100 ml (N = 9) to 85 ± 7 mg/100 ml (N = 12). CGS8515 did not alter the endotoxin-induced increase of plasma immunoreactive thromboxane B₂ levels at either 30 min or 4 hr postendotoxin injection, but significantly reduced (P < .05) the increase in plasma immunoreactive 6-keto-prostaglandin F(1α) at the 4-hr postendotoxin injection. Histologic examination demonstrated that CGS8515 prevented the congestion of the villi capillary plexus in the small intestines, periportal damage to hepatocytes and pulmonary sequestration of neutrophils. The beneficial effects of CGS8515 during endotoxic shock in the rat suggest that lipoxygenase products are significant pathophysiologic mediators of this syndrome.