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Adenosine and the regulation of cerebral blood flow
From Neurological Research, 3/1/05 by O'Regan, Michael

Objectives: This review summarizes the 30 year effort of my collaborator and mentor Dr J. W. Phillis to establish the role of adenosine in the regulation of cerebral blood flow.

Methods: While most of the experiments described utilized the rat cerebral cortex as a model, several different and complementary methodologies were employed. Superfusate samples were collected from the cortical surface and analysed for purines using HPLC. Laser-Doppler flowmetry was utilized to measure blood flow in the pial vasculature, while pial diameters were monitored by videomicroscopy. An additional series of experiments looked at coronary blood flow in a Langendorff preparation.

Results: Adenosine is released from the cortex in response to decreased nutrient supply (hypoxia/ ischemia) and during conditions that mimic alterations in the extracellular environment associated with increased metabolism. The application of pharmacological agents that alter adenosine metabolism resulted in the appropriate alterations in ECF adenosine levels and also in blood flow. Selective blockade of the adenosine A^sub 2A^ receptor reduced the pial vasodilation evoked by hypercapnoea. Results from the isolated rat heart, utilizing similar agents, support a role for adenosine in the regulation of coronary blood flow during respiratory and metabolic acidosis.

Discussion: Adenosine is released when there is a mismatch between supply and demand. If the effects of adenosine are blocked with receptor antagonists, the vasoailation is also reduced. However, the effects of adenosine on the hyperemia evoked by hypercapnoea are complicated by the arousal evoked by adenosine receptor antagonists and the effects of upstream regulation. [Neurol Res 2005; 27: 175-181]

Keywords: Adenosine; hypercapnoea; cerebral blood flow; nitric oxide; coronary blood flow

The fundamental regulator of blood flow is tissue need. As metabolism increases, tissue requirement for substrate (oxygen and glucose) increases. Conversely, decreases in supply would also necessitate an increase in blood flow. The metabolic regulation of cerebral blood flow is well documented1,2. This matching between blood flow and metabolism implies the presence of a mediator or mediators. The identification of this mediator in the cerebral circulation has been a reoccurring focus of the research of Dr J. W. Phillis over the past 30 years. A putative mediator needs to meet this basic requirement: it should be released in response to supply/demand mismatches and then act to restore the balance. One proposed mediator is the endogenous vasodilator adenosine3,4.

Basically, there were several points that needed to be established. First, that adenosine is released in sufficient quantities from the cortex, in response to mismatches between supply and demand. The application of agents that modify adenosine metabolism and release should result in appropriate changes in the ECF levels of adenosine. Also, the application of these agents should therefore cause appropriate changes in cerebral blood flow. Finally, the identity of the adenosine receptor that mediates the response needed to be established. Additionally, we examined parallel responses in the coronary circulation. This review recounts our attempts to solidify the role of adenosine as an important regulator of cerebral blood flow.

Early work established the release of labeled adenosine and adenosine triphosphate from the cat5 and rat6,7 cortex. In response to a 5 minute period of 8% oxygen inhalation (Figure 1, from Phillis et al.8), there was an accompanying fall in blood pressure with a significant release of endogenous adenosine into a cortical cup positioned upon the rat cortex. The release of adenosine was especially pronounced in the first recovery period, and then returned to basal levels. Hypotension, in the absence of hypoxia, failed to evoke release. Anoxia evoked an even greater release of adenosine and its metabolite inosine. It is likely that, when oxygen supply became inadequate, cells were unable to maintain ATP levels, with a subsequent metabolism to adenosine. We failed to discern appreciable increases in the superfusate levels of nucleotides under hypoxic conditions9, indicating that it was adenosine itself that was released following the ICF metabolism of ATP. There are two major classes of purine transporters-equilibrative (ENT1 and ENT2) and concentrative (CNT1 and CNT2). The equilibrative transporters are bi-directional, a fact that complicates the interpretation of transport blocker results. Thus, while soluflazine (0.05 mg/kg iv or 10^sup -5^ M) suppressed hypoxia-evoked purine release, dipyridamole potentiated the accumulation of adenosine into cortical superfusates10. Two other putative transport inhibitors, nifedipine and felodipine, depressed both basal and hypoxia/ischemia-evoked release of adenosine and inosine11. These discrepancies may be due to differences in subtype selectivity, or the relative ability of transport inhibitors to block either purine efflux or influx.

Ischemia, whether induced by 20 minutes of fourvessel occlusion (Figure2, from Phillis et al.12) or middle cerebral artery occlusion13 evoked a significant release of adenosine and its metabolites. In both cases, the superfusate levels of adenosine rapidly returned towards baseline following reperfusion, probably as a result of re-incorporation into adenine nucleotides. Indeed, cortical ATP re-synthesis occurs rapidly following a 20 minute period of forebrain ischemia14. If the period of four-vessel ischemia was extended to 40 minutes, both adenosine and inosine achieved comparable increases, yet remained elevated following reperfusion, indicating a failure to re-establish ATP synthesis15. However, extending the period of middle cerebral artery occlusion to 60 minutes evoked an adenosine release that still returned to baseline levels13.

In the normoxic brain, adenosine is taken up by neurons and glia, and primarily converted back to AMP after phosphorylation by adenosine kinase. Alternatively, the adenosine can be metabolized by adenosine deaminase. The inhibition of either pathway should result in the elevation of ECF adenosine levels. Application of the adenosine deaminase inhibitor deoxycoformycin (500 µg/kg), significantly enhanced both hypoxia and ischemia-evoked17 release of adenosine into cortical superfusates, while inosine and hypoxanthine release was suppressed. Deoxycoformycin also enhanced ATP recovery following ischemia18, indicating an enhancement of purine salvage.

Thus, it is apparent that reductions in the supply of substrate to the brain, either by the induction of hypoxia or ischemia results in a reversable release of adenosine into the extracellular compartment. Aside from transport inhibitors, pharmacological inhibition of adenosine metabolism results in predictable elevations of ECF adenosine. In response to hypoxia/ischemia, sufficient concentrations of adenosine are achieved in the extracellular space to dialate the pial vasculature in an attempt to increase supply. On the demand side of the equation, an increase in metabolism can result in elevated ECF levels of potassium and carbon dioxide, and a reduction in ECF pH. Cell swelling may occur as a consequence of metabolic failure, cellular depolarization or intracellular acidosis. We investigated the effects of these indicators of metabolic activity on the release of adenosine from the rat cerebral cortex.

Topical application of 75 mM KCI (but not 50 mM) elicited a small, but significant release of adenosine and inosine into cortical cup superfusates19. These releases were minimal when compared to those evoked by ischemia (50% increase versus 500%), indicating that even with the increase in energy demand created by the elevated potassium levels, no cortical energy failure was apparent. Indeed, during status epilecticus, with an increased energy utilization to about 250% of control, ATP levels are maintained20. This result might also argue against extracellular adenosine formation following exocytotic release of ATP, since the release of traditional neurotransmitters (such as GABA) is quite sensitive to even low concentrations (50 mM) of KCI.

Cell swelling may occur as a consequence of a loss of volume regulation during energy failure or as a result of electrical stimulation or potassium-induced depolarization. Exposure of the rat cerebral cortex to brief periods of hypotonie (25 mM NaCI) solutions evoked a significant release of adenosine, but not adenine nucleotides21. This required a much stronger stimulus than that required to evoke a regulatory volume decrease response, as evidenced by the release of taurine following exposure to a 50 mM NaCI solution22. The release of adenosine required the same level of hyposmotic challenge that causes the release of glutamate and aspartate, and presumably depolarization. Cell swelling can also be a result of acidosis, which induces a net uptake of sodium. Exposure of cells to monocarboxylates leads to intracellular acidosis as a consequence of their entry via H^sup +^ -monocarboxylate co-transporters. The application of isotonic solutions of sodium L-lactate or acetate (both 20 mM) evoked small, but significant, releases of AMP and ADP, but not ATP or adenosine23. Pyruvate only increased ADP levels. It would appear that acidification of cells, in the absence of metabolic disturbances, does not significantly induce adenosine release. However, the application of the non-metabolite D-lactate (20 mM), which is also cotransported with H^sup +^, induced a 2.6-fold increase in superfusate adenosine levels. Cellular metabolism also increases the local PCO^sub 2^. Variations in arterial CO2 levels have marked effects on cerebrovascular flow. Hypercapnoea results in arterial dilation and an elevated cerebral blood flow, whereas hypocapnoea causes constriction and a reduction in flow. This affect appears to be independent of arterial pH24. We investigated the ability of an 8 minute period of 10% CO2 inhalation to enhance adenosine release into cortical superfusates. This level of hypercapnoea evoked a small but significant increase in adenosine levels (Figure 3, from Phillis and O'Regan25).

It is obvious that to obtain very large releases of adenosine requires an interruption of metabolism, as evidenced by our results with hypoxia and ischemia. More physiological interventions associated with increases in activity result in much smaller releases. Are these approximately two-fold increases in superfusate adenosine levels large enough to significantly increase blood flow? Overall, in our cortical cup experiments basal levels of superfusate adenosine range between 20 and 50 nM, close to our limits of detection. Adenosine levels in normal CSF collected from rat cisterna magna averaged 32±8nM8, while plasma adenosine levels in the rat are 79 + 13 nM26. The threshold for the dilation of coronary arteries by adenosine is about 70 nM27. Adenosine applied topically onto exposed cerebral subpial vessels readily causes dilation at doses as low as 10^sup -7^ M28. This would indicate that adenosine should have little effect on basal CBF; indeed, the application of adenosine receptor antagonists does not affect basal CBF or pial vessel diameter29,30. However, even a doubling of ECF adenosine levels may significantly dilate pial arterioles and increase CBF. The next section of this review focuses on the mediator role of adenosine in hypercapnoea-evoked hyperemia in the rat cerebral cortex.

The systemic application of caffeine (a non-selective adenosine receptor antagonist) significantly inhibited CO2-evoked increases in CBF recorded in a rat venous outflow model31, while adenosine potentiators, dipyridamole (an uptake inhibitor) and deoxycoformycin (an adenosine deaminase inhibitor) enhanced peak flow rates during hypercapnoic episodes. Topically applied adenosine deaminase, attenuated arteriolar dilation during hypercapnoic episodes in the rat32. Conversely, the application of a different non-selective adenosine receptor antagonist, theophylline, failed to significantly block the CO2-evoked hyperemia33-36. One complication to these studies is the possibility of cortical arousal following the application of non-selective adenosine receptor antagonists, which would increase CBF in association with increased neuronal activity. Hypercapnoea can also elicit cortical arousal.

The vasodilatory actions of adenosine on intracerebral arterioles are mediated by the A^sub 2A^ receptor subtype37. Systemically administered caffeine (10 mg/kg), and the selective adenosine A^sub 2A^ receptor antagonist 9-chloro2-furanyl-5,6-dihydro-1,2,4-triazolo[1,5-clquinazoline-5imine (CGS 15943, 0.1 mg/kg), attenuated CO2-evoked increases in cerebral cortical blood flow measured by laser-Doppler flowmetry (Figure 4, from Estevez and Phillis38. Caffeine did not affect normocapnoic basal CBF. Administration of NG-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg, a non-selective nitric oxide synthase inhibitor) also inhibited the hypercapnoic hyperemia. The effects of caffeine and L-NAME appeared to be additive. One limitation of this study was that the route of application (systemic) did not distinguish between effects at several different levels, including the CNS, the autonomie nervous system, and the upstream vasculature.

Topical application of the selective adenosine A^sub 2A^ receptor antagonist 4-{2-[7-amino-2-(2-furyl)(1,2,4) triazolo(2,3-a)triazin-5-y1-amino]ethyl} phenol (ZM 241385) failed to attenuate the CO2-induced cortical hyperemia, again measured by laser-Doppler flowmetry, unless its application was preceded by systemically administered L-NAME Figure 5, from Phillis and O'Regan25). A potential explanation for this difference may be that systemically administered inhibitors were able to affect flow through the major cerebral resistance arteries, with a decrease in flow rate through the small superficial pial arterioles recorded by the laser-Doppler probe. Although topically applied inhibitors could decrease superficial arteriolar diameter, a failure to decrease flow through the major resistance vessels would have sustained or even enhanced flow rates through the superficial cortical arterioles. To further examine this possibility, we directly measured pial arteriolar diameter using videomicroscopy through a rat cranial window.

Inhalation of 10% carbon dioxide for 80 seconds resulted in a significant, 17.8 + 0.8%, increase in arteriolar diameter. Under resting conditions, CO2 reactivity (percentage change in arteriolar diameter/ mmHg increase in p^sub a^CO^sub 2^) was 1.23 ± 0.1%/mmHg and pH reactivity (the percentage change in diameter per change in pH units) was 144 ± 9%/pH unit. The pH reactivity estimates take into account the possibility that a fraction of the vascular response to hypercapnoea could be due to the release of endothelium-derived vasoactive compounds. Topical application of ZM241385 (1 µM) had no effect on resting MABP, blood pH; PaCO^sub 2^, PaO^sub 2^ or arteriolar diameter. However, it significantly depressed the CO2-evoked increase in arteriolar diameter, as well as attenuating the CO2 and pH reactivity of the cortical arterioles (Figure 6, from Phillis et al.19). Recovery of the CO2-evoked response became apparent following cessation of ZM-241385 application. Similarly, topical application of 5-amino-7[2-phenylethyl]-2-(2-furyi)-pyrazolo(4,3-e)-1,2,4-triazolo (1,5-c)pyrimidine (SCH 58261; 100nM) depressed arteriolar responses to CO2-inhalation. The effects of SCH 58261 were also reversible following washout. LNAME (1 mM), which was without effect on resting cortical arterioles, significantly depressed the hypercapnoea-evoked increase in their diameter, as well as attenuating the CO2, but not the pH, reactivity.

Thus, the topical administration of both selective adenosine A^sub 2A^ receptor antagonists and the inhibition of nitric oxide synthase can reduce, but not block the dilation of pial arterioles evoked by CO2. This result appears to conflict with the inability of topical application of these agents to significantly affect the hypercapnoic hyperemia. However, following the systemic administration of L-NAME, topical caffeine and ZM241385 significantly reduced the hypercapnoeaelicited increase in flow. The lack of effect on CBF in response to hypercapnoea, in the presence of an intact NO signaling pathway, appears to indicate a redundancy in the regulation of CBF. However, when ZM241385 and L-NAME were co-applied topically, the CO2-evoked increase in flow was not reduced25, indicating that the primary effect of systemic L-NAME was occurring elsewhere. A noticeable effect of systemic, but not of topical L-NAME administration was that CBF declined appreciably, in spite of an increase in arterial blood pressure, which could indicate that arterial resistance had increased upstream in the major arterioles. The regulation of CBF may involve three mechanisms, which together co-ordinate the overall response of the vasculature from upstream arteries to downstream arterioles40. Small terminal arterioles (

As a corollary to the results on CBF, we undertook a series of experiments utilizing an isolated perfused rat heart preparation. This removed the complication of a portion of the hyperemia possibly being due to cortical arousal evoked by either CO2 or the application of adenosine receptor antagonists. Exposure of the hearts to a hypercapnoic perfusion solution (equilibrated with 10% CO2) resulted in an increase in flow to 130±4%of basal. Additions of either erythro-9-(2-hydroxy-3-nonyl) adenosine (EHNA, µM, an adenosine deaminase inhibitor) or 5-iodotubercidin (1 µM, an inhibitor of adenosine kinase), to the perfusate resulted in significant increases in the hyperemic response to elevated CO2, which was reversible upon washout of the drugs (Figure 7, from Phillis et al.42. Whilst the administration of adenosine deaminase (1 U/ml) significantly reduced the hypercapnoea-evoked hyperemia. Adenosine kinase and adenosine deaminase have previously been shown to be the major regulators of adenosine levels in the heart43,44. These results support the role of endogenous adenosine as an important mediator of CO2-evoked increases in coronary flow. Dipyridamole (1 µM), an adenosine transport inhibitor, doubled the coronary flow during hypercapnoic acidosis. The application of both non-selective (50 µM caffeine and 100nM 8phenyltheophyline) and selective adenosine A^sub 2A^ receptor antagonists ZM241385 (at 10 and 100 nM) and SCH 58261 significantly reduced the hyperemia associated with either hypercapnoic or metabolic (pH 6.97) acidosis (Figure 8, from Phillis et al.45). As expected, the administration of a selective adenosine A^sub 1^ receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine; 10 nM) had no effect. Of interest, prior administration of the nitric oxide synthase inhibitor L-NAME (100 µM) reduced the basal, resting rate of coronary flow without affecting the hyperemia evoked by either hypercapnoea or metabolic acidosis.

In conclusion, the evidence has accumulated that adenosine is released into the extracellular space of the rat in response to either reductions in supply (hypoxia/ ischemia) and under conditions that are associated with an increase in metabolism (high K+ , acidosis, hypotonicity and hypercapnoea). Although basal levels of adenosine are likely to be insufficient to contribute to basal arteriolar tone, evoked releases of adenosine, acting through adenosine A^sub 2A^ receptors, can result in vasodilation. Pharmacological manipulations that alter the ECF levels of adenosine appropriately modify the CBF response to hypercapnoea. These results from the cerebral vasculature are further supported by comparative data from the coronary circulation. Overall, there now exists considerable evidence that adenosine is an endogenous mediator between cerebral metabolism and blood flow.


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Michael O'Regan

Department of Biomedical Sciences, School of Dentistry, University of Detroit Mercy, 8200 W. Outer Drive, P.O. Box 19900 Detroit, Ml 48219-0900, USA

Correspondence and reprint requests to: M. O'Regan, Department of Biomedical Sciences, School of Dentistry, University of Detroit Mercy, 8200 W. Outer Drive, P.O. Box 19900 Detroit, Ml 48219-0900, USA. [oreganmh@udmercy.edu] Accepted for publication.

Copyright Maney Publishing Mar 2005
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