Effects of Epidural Epinephrine on the Spinal Cord Accumulation of Epidural Clonidine in Rabbits

Abstract

In Response: Due to an oversight, it was mentioned that sodium fluorescein was administered into the lateral ventricle along with epinephrine and norepinephrine in the article cited [1], whereas sodium fluorescein was administered IV [2], as was rightly pointed out by Mori et al. [3]. The statement that sodium fluorescein was administered IV should serve as a correction to future readers our article. In our opinion, there is no misinterpretation of the data due to this discrepancy. The focus of this study was permeability of [(3) H]-clonidine HCl across the blood-spinal cord barrier (BSCB), i.e., from the blood to the central nervous system tissue (apical to basal direction across the endothelium). The conclusions drawn originally were based on the hypothesis and data that co-administration of epinephrine increases the uptake of [(3) H]-clonidine HCl into the lumbar cord through an alpha-adrenergic-mediated increase in vascular endothelial permeability. The following statements should clarify certain points regarding alpha-adrenergic stimulation of the blood-brain barrier (BBB) [2] and how it relates to our study [1]. The epinephrine and norepinephrine were administered into the lateral ventricle to achieve the concentrations in the vasculure of the cerebral cortex required to exert its pharmacological action. IV administration of sodium fluorescein, the uptake of which is used as a marker to study the permeability across the BBB. The increased cerebral extraction ratio observed was concluded to be due to pinocytotic activity mediated through alpha-adrenergic stimulation. In our study, epinephrine (1:200,000 diluted) was co-administered with lipophilic [(3) H]-clonidine HCl for 90 min into the epidural space, and its uptake into 11 segments of the lumbar cord was determined by radiometry. Data presented in our original Figure 2RF 1* shows a bell-shaped curve, indicating significant uptake of [(3) H]-clonidine HCl at the site of the administration/epidural catheter placement (midlumbosacral cord) compared with controls. A similar observation of an epinephrine-induced increase in uptake of hydrophilic compounds, e.g., [(3) H]-D-mannitol and [(14) C]-carboxyl-inulin, was reported earlier [4]. Our observation consistently provides evidence that the increased up-take of [(3) H]-clonidine HCl, at least in part, is due to alpha-adrenergic stimulation by epinephrine. The precise route of transfer of [(3) H]-clonidine HCl across the vascular endothelium may be due to alpha-adrenergic receptor-stimulated pinocytosis. Because of similarities in the experimental approach, Sermento et al.'s [2,5] studies add credence to our observation. Further confirmation of this mechanism in our model is under investigation. We have reported that the BSCB is more permeable than the BBB and that there are regional differences in permeability in the spinal cord [6]. The degree of differences in permeability are as follows: the lumbar cord is the most permeable, the thoracic is the least, and the cervical is intermediate. Based on this observation, we conclude that the placement of catheter-in this case, the lumbar cord, a frequent site for epidural administration-is more permeable than other regions of the spinal cord. Further understanding of this process in different regions of the spinal cord, e.g., thoracic and/or cervical cord, was not within the scope of the study cited [1]. The alpha-adrenergic-mediated pinocytotic activity is a dose-dependent process [2], and larger doses of epinephrine/norepinephrine may potentiate the analgesic effect. Further studies on regional differences, the dose of epinephrine, and the choice of antioxidant (addition of ascorbic acid versus sodium metabisulfite to prevent the degradation of epinephrine) are underway to elucidate the pharmacological/physiological role of epinephrine in increasing the uptake of epidural agents across the BSCB. Kamatham A. Naidu, PhD Eugene S. Fu, MD Leon D. Prockop, MD Departments of Neurology and Anesthesiology; College of Medicine; University of South Florida; Tampa, FL 33612