Melatonin and a 21-aminosteroid attenuate shock after hemorrhage but differentially affect serum cytokines

Melatonin and 21-aminosteroids (lazaroids) are potent antioxidants and may attenuate the increased membrane permeability associated with profound shock. Our purpose was to test the effect of melatonin and a lazaroid (U74389-G) on cytokine production and fluid requirements after shock.

Male C3H/HeN mice, 20-25 g, were hemorrhaged via a femoral artery catheter to a mean arterial pressure of 35 +/- 5 mm Hg, which was maintained for 1 hr, and then resuscitated with shed blood and crystalloid (2x vol of shed blood). Experimental mice received melatonin at 10 or 50 mg/kg, U74389-G at 3 mg/kg, or vehicle i.v. upon resuscitation, and blood was returned at 0.1 cc/min and crystalloid at 0.05 cc/min. The percentage of total crystalloid required to reach stabilization (mean arterial pressure remaining within 2 mm Hg for 5 min) was recorded. Animals were sacrificed at 1 hr postshock. Serum and anti-CD3-stimulated splenocyte culture supernatants were assayed for interleukin-6 (IL-6) and gamma-IFN by ELISA.

Mice receiving lazaroid or melatonin (50 mg/kg) required significantly less fluid to reach stabilization, with lazaroid-treated animals requiring 24 +/- 1% and melatonin-treated animals requiring 28 +/- 2% of total crystalloid compared to 40 +/- 3% for untreated animals. Melatonin-treated mice (50 mg/kg) had lower serum IL-6 levels (368 +/- 154 vs 1078 +/- 146 pg/ml) and lazaroid-treated mice had lower gamma-IFN levels (7 +/- 6 vs 52 +/- 15 pg/ml) compared to those of the untreated group (P < 0.05). There were no differences in splenocyte cytokine production.

Treatment with lazaroid and melatonin both reduced postshock fluid requirements. Melatonin reduced serum IL-6 levels, while lazaroid reduced serum gamma-IFN levels, suggesting different mechanisms of action.