Partial antagonistic effect of adenosine on inverse coupling between spreading neuronal activation and cerebral blood flow in rats

Introduction: Fundamental principles in the central nervous system are that primary depolarization of neurons causes hyperemia, whereas focal cerebral ischemia causes secondary neuronal depolarization. In rats, an exception to these rules was discovered recently in which primary neuronal depolarization led to focal cerebral ischemia via inverse coupling between neuronal metabolism and cerebral blood flow (CBF). Adenosine is one of the classical candidate factors to mediate the coupling between neuronal metabolism and CBF. Therefore, the effect of topically applied adenosine on cortical spreading ischemia was studied. Methods: A cranial window was implanted in 10 rats. At the window, CBF (laser Doppler flowmetry) and the subarachnoid direct current potential were recorded; the cortical surface was superfused with artificial cerebrospinal fluid (ACSF). A spreading neuronal/ astroglial depolarization wave was triggered at a remote site, from which it propagated to the cranial window. Results: In all rats, the depolarization wave triggered a hyperemic event under physiological conditions. When ACSF containing the nitric oxide (NO)synthase inhibitor N-G-nitro-L-arginine (L-NNA) at 10(-3) M and K+ at 20 x 10(-3) M was subsequently superfused, the depolarization wave triggered an ischemic event. In 5 of 10 animals, a second depolarization wave under L-NNA and elevated K+ also triggered an ischemic event. In contrast, in the remaining five animals, the depolarization wave triggered a significantly smaller and shorter hypoperfusion when adenosine at 100 mu M was coapplied with L-NNA and elevated K+. Conclusion: The results of this study suggest that adenosine, like other vasodilators, is unable to antagonize the initial hypoperfusion in response to a spreading neuronal/astroglial depolarization wave when the NO concentration is reduced and K+ is elevated but shortens the hypoperfusion phase significantly.