Effect of caffeine on theophyliine on cerebral blood flow response to brain activation: In vitro and in vivo studies

Despite its wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine, an adenosine receptor antagonist, on neurovascular coupling. In the present study, we evaluated the effects of caffeine on intracerebral arterioles in vitro and on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50uM) on vasodilatation induced by extraluminal application of adenosine. Adenosine caused dose-dependent dilations. Pretreatment with caffeine alone, at either of the concentrations tested, had no effect on resting diameter. The higher concentration (50uM) of caffeine resulted in significant attenuation of adenosine-induced vasodilatation (p<0.05, n=5), whereas 10uM had no effect. We utilized reverse-phase HPLC to quantify in vivo CSF caffeine concentrations. Intravenous administration of 5 mg/kg caffeine led to CSF concentrations of approximately 3uM, whereas higher doses (10 and 40 mg/kg), resulted in CSF caffeine accumulations of more than 10 and 60uM, respectively (n=18). To study the effect of caffeine on neurovascular coupling, we created a close cranial window in anesthetized, ventilated and temperature-regulated rats. Pial arteriolar response to contralateral sciatic nerve stimulation (SNS) was then evaluated before and after intravenous administration of caffeine (5, 10, 20 30 & 40 mg/kg). Contralateral SNS resulted in a 23.8% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose (5 mg/kg), equivalent to 2 cups of brewed coffee, had no effect on resting arteriolar diameter but slightly suppressed the arteriolar response to somatosensory stimulation. This trend, however, did not reach statistical significance. At all of the higher doses (10, 20, 30 & 40 mg/kg, i.v.), caffeine significantly attenuated the cerebral blood flow responses to contralateral SNS (Figure 1; p<0.05; n=6). Caffeine administration also significantly reduced resting arteriolar diameter. In contrast, hypercarbic vasodilatation was unaffected by caffeine at any of the doses tested. The results of the present study demonstrate that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.