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

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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, PaCO2, PaO2, 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), adrenomedullin22–52, 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.