Intravenous Infusion of Adrenomedullin and Increase in Regional Cerebral Blood Flow and Prevention of Ischemic Brain Injury after Middle Cerebral Artery Occlusion in Rats

Abstract

The intravenous infusion of rat adrenomedullin, at concentrations ranging from 0.1 to 1.0 μg/kg/min, for 60 min increased the regional cerebral blood flow (rCBF) in a dose-dependent manner in rats. rCBF was measured using a laser Doppler flowmetry device placed on the surface of the parietal cortex. The increase in rCBF induced by 1.0 μg/kg/min of adrenomedullin was up to 145 ± 10.8% of controls at 60 min (n = 5, p < 0.001). These concentrations of adrenomedullin did not affect systemic blood pressure or other physiologic parameters, including pH, P_aCO₂, P_aO₂, hemoglobin, and blood glucose. Repeated infusion of 1.0 μg/kg/min of adrenomedullin at 2-h intervals caused tachyphylaxis (n = 5, p < 0.01). Rat adrenomedullin (1.0 μg/kg/min) demonstrated a more potent effect than the same dose of human adrenomedullin. The C-terminal fragment of human adrenomedullin (0.5 and 5.0 μg/kg/min), adrenomedullin_22–52, which did not affect rCBF alone, inhibited the effect of rat adrenomedullin (0.5 μg/kg/min) as a receptor antagonist in a dose-dependent manner. In a model of middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats, pre- and postinfusion of 1.0 μg/kg/min of adrenomedullin suppressed the reduction in rCBF following MCA occlusion (control, 29 ± 15.1%; adrenomedullin group, 45 ± 14.4%; not significant) and decreased the volume of ischemic brain injury (control, 288 ± 35 mm³; adrenomedullin group, 232 ± 35 mm³; p < 0.05). These results suggest that adrenomedullin increases rCBF and prevents ischemic brain injury, partly by increasing the collateral circulation.