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We recently reported that cerebral and cardiac injuries are mitigated in immature female piglets after severe hemorrhage with subsequent cardiac arrest. Female sex was also associated with a smaller increase in the cerebral expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). In the current study, we tested the hypothesis that exogenously administered 17β-estradiol (E₂) can improve neurological outcome by NOS modulation. Thirty-nine sexually immature piglets were bled to a mean arterial pressure of 35 mmHg over 15 min. Fifty micrograms per kilogram of E₂ was then administered to 10 male and 10 female animals (estradiol group), whereas control animals (n = 10 males and 9 females) received equal volume of normal saline. The animals were then subjected to ventricular fibrillation (4 min) followed by up to 15 min of open-chest cardiopulmonary resuscitation. Vasopressin 0.4 U · kg⁻¹ and amiodarone 0.5 mg · kg⁻¹ were given, and 3 mL · kg⁻¹ of 7.5% saline with 6% dextran was administered over 20 min. All surviving animals were killed after 3 h, and their brains examined for histological injury and NOS expression. No significant differences were observed in survival or hemodynamics between the groups. Compared with the control group, animals in the E₂ group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption, and a mitigated neuronal injury. There was a significant correlation between nNOS and iNOS levels and neuronal injury. Interestingly, estradiol attenuated cerebral damage (including lower activation of nNOS and iNOS) both in male and female piglets. In conclusion, in our immature piglet model of hypovolemic cardiac arrest, E₂ downregulates iNOS and nNOS expression and results in decreased blood-brain-barrier permeability disruption and smaller neuronal injury.
Semenas et al. (Thu,) studied this question.