Adrenomedullin and the blood-brain barrier

Adrenomedullin (ADM) is present both in the periphery and brain. In additio n to its peripheral effects, this peptide can exert central effects such as decreasing food ingestion. We used multiple-time regression analysis to de termine that labeled ADM can cross from blood to brain with an apparent inf lux constant (K-i) of 5.83 +/- 1.44 x 10(-4) ml/g-min, much faster than tha t of albumin, the vascular control. HPLC showed that almost all of the inje cted I-125-ADM in the brain was intact, and capillary depletion showed that it could reach the parenchyma of the brain. However, more I-125-ADM was re versibly associated with the brain vasculature than we have seen with any o ther peptide tested by these methods. After intracerebroventricular injecti on, I-125-ADM exited the brain with the bulk reabsorption of cerebrospinal fluid at an efflux rate comparable to that of albumin. Although there was n o blood-to-brain saturation, in situ brain perfusion of I-125-ADM in blood- free physiological buffer showed self-inhibition by excess unlabeled ADM. T his, along with evidence of the lack of protein binding shown by capillary zone electrophoresis, indicated competition for the binding site of ADM at the BBB. The low lipophilicity of ADM determined by the octanol/buffer part ition coefficient was also consistent with the prominent reversible associa tion of ADM with the vasculature of the BBB. This suggests a function for A DM at the cerebral blood vessels, such as altering cerebral blood flow and perfusion, without disruption of the BBB.