The Effect of Local Infusion of Adenosine and Adenosine Analogues on Local Cerebral Blood Flow

Abstract

The purpose of this study was to determine the effects of local infusion of adenosine (ADO) and non-metabolized ADO analogues on local cerebral blood flow (CBF) and interstitial fluid (ISF) ADO levels. The brain dialysis technique was used to (a) deliver drugs locally to brain tissue, (b) estimate cerebral ISF ADO levels, and (c) measure local CBF (hydrogen clearance). Dialysis probes were implanted bilaterally in the caudate nuclei of ketamine-anesthetized rats. The probe on one side was perfused with artificial CSF while the contralateral probe was perfused with artificial CSF containing ADO ( n = 5), or the ADO agonists 2-chloroadenosine (2-CADO; n = 4) or 5'-N-ethylcarboxamide adenosine (NECA; n = 4). When ADO was included in the artificial CSF at 10−5, 10−4, or 10−3 M, a 30% increase in local CBF was detected only with 10−3 M ADO. During perfusion with ADO, dialysate inosine and hypoxanthine levels increased, indicating that the cells adjacent to the probe metabolized the exogenous ADO. With 2-CADO included in the artificial CSF at 10−6, 10−5, or 10−4 M, local CBF increased 18, 131, and 201%, respectively. Perfusion with artificial CSF containing 10−7, 10−6, or 10−5 M NECA resulted in a 35, 112, and 187% increase in local CBF, respectively. In a separate group of rats ( n = 6), perfusion with artificial CSF containing 10−6 M NECA resulted in a sustained twofold increase in local CBF and 40% decrease in dialysate adenosine concentration, both of which could be reversed by including 8-( p-sulfophenyl)-theophylline, an ADO receptor antagonist, in the artificial CSF. These results are consistent with the known vascular actions of ADO and ADO analogues and suggest that there is a basal level of ISF ADO that can be reduced by increased CBF and/or adenosine receptor activation.