Preservation of Cerebral Vascular Reactivity by Sodium Channel Inhibition in Experimental Acute Prolonged Hypotensive Hypoxic Injury (HI) in Newborn Pigs

Abstract 1217 Neonatal Disease Oriented Research: Molecular Events and Brain Injury Poster Symposium, Tuesday, 5/4

Sodium channels universally distributed in CNS cerebral vasculature have been shown to be important in regulation of normal brain metabolism, function, and vascular reactivity. Since an alteration of cerebral hemodynamics almost always accompanies substantial HI, preservation of cerebral vascular reactivity can be very important in neuroprotection. Fluctuation of cAMP level in CSF correlates with the degree and duration of HI and has been suggested as a possible indicator of altered cerebral vascular reactivity and metabolism. We hypothesize that sodium channel inhibition before or at the end of experimental HI in newborn pigs will protect cerebral vascular reactivity and maintain CSF cAMP levels. Three groups of piglets with closed cranial window were studied: asphyxia group (n=5) and 2 treatment groups. Pigs were treated with 50 mg/kg I.V. sodium channel blocker HOE642 (cariporide mesilate) before (n=6) or at the end of asphyxia (n=6). Asphyxia was sustained over 60 min by ventilating piglets with 10% O2 gas mixture and by decreasing the minute volume while maintaining systemic BP around 30 mm Hg and the heart rate of 50-80 bpm, with subsequent reventilation. Pial arteriolar diameters were recorded, and CSF was collected for cAMP measurements every 10 min. Vascular reactivity to topically applied isoproterenol (10^-4M) was evaluated at 60 min of recovery. Groups did not differ as to BP, pH and ABG values at baseline, asphyxia and reventilation. The table shows % changes in pial arteriolar diameters and CSF cAMP over baseline (*p<0.05 compared to baseline).

Table 1 No caption

We observed attenuated changes in vascular tone, CSF cAMP concentrations, and improved restoration of vascular reactivity in newborn pigs treated with sodium channel blockers either before or immediately after experimental HI. Thus, pharmacological modulation of sodium channels may be a new, promising therapeutic modality in HI brain injury.