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Fatima A. Sehba, Rowena Flores, Artur Muller, Victor Friedrich, Jiang-Fan Chen, Gavin W. Britz, H. Richard Winn, and Joshua B. Bederson

Object

The role of adenosine A2A receptors in the early vascular response after subarachnoid hemorrhage (SAH) is unknown. In other forms of cerebral ischemia both activation and inhibition of A2A receptors is reported to be beneficial. However, these studies mainly used pharmacological receptor modulation, and most of the agents available exhibit low specificity. The authors used adenosine A2A receptor knockout mice to study the role of A2A receptors in the early vascular response to SAH.

Methods

Subarachnoid hemorrhage was induced in wild-type mice (C57BL/6) and A2A receptor knockout mice by endovascular puncture. Cerebral blood flow, intracranial pressure, and blood pressure were recorded, and cerebral perfusion pressure was deduced. Animals were sacrificed at 1, 3, or 6 hours after SAH or sham surgery. Coronal brain sections were immunostained for Type IV collagen, the major protein of the basal lamina. The internal diameter of major cerebral arteries and the area fraction of Type IV collagen–positive microvessels (< 100 μm) were determined.

Results

The initial increase in intracranial pressure and decrease in cerebral perfusion pressure at SAH induction was similar in both types of mice, but cerebral blood flow decline was significantly smaller in A2A receptor knockout mice as compared with wild-type cohorts. The internal diameter of major cerebral vessels decreased progressively after SAH. The extent of diameter reduction was significantly less in A2A receptor knockout mice than in wild-type mice. Type IV collagen immunostaining decreased progressively after SAH. This decrease was significantly less in A2A receptor knockout mice than in wild-type mice.

Conclusions

These results demonstrate that global inactivation of A2A receptors decreases the intensity of the early vascular response to SAH. Early inhibition of A2A receptors after SAH might reduce cerebral injury.

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Grzegorz Miekisiak, Kristen Yoo, Adam L. Sandler, Tobias B. Kulik, Jiang-Fan Chen, and H. Richard Winn

Object

The authors tested the hypothesis that adenosine, acting through the A2A receptor, is not involved in hypercarbic hyperemia by assessing the effects of increased PaCO2 on cerebral blood flow (CBF) in vivo in wild-type and A2A receptor knockout mice. In addition, they evaluated the effect of abluminal pH changes in vitro on the diameter of isolated perfused penetrating arterioles harvested from wild-type and A2A receptor knockout mice.

Methods

The authors evaluated in a blinded fashion the CBF response during transient (60-second) hypercapnic (7% CO2) hypercarbia in anesthetized, ventilated C57Bl/6 wild-type and adenosine A2A receptor knockout mice. They also evaluated the hypercarbic response in the absence and presence of the nonselective and selective adenosine antagonists.

Results

Cerebral blood flow was measured using laser Doppler flowmetry. There were no differences between the CBF responses to hypercarbia in the wild-type and the knockout mice. Moreover, the hypercarbic hyperemia response was not affected by the adenosine receptor antagonists. The authors also tested the response to alteration in abluminal pH in isolated perfused, pressurized, penetrating arterioles (average diameter 63.3 ± 3.6 μm) harvested from wild-type (6 mice) and knockout (5 mice) animals. Arteriolar dilation in response to a decrease in abluminal pH, simulating the change in vivo during hypercarbia, was similar in wild-type (15.9 ± 2.6%) and A2A receptor knockout (17.7 ± 1.3%) mice. With abluminal application of CGS 21680 (10−6 M), an A2A receptor agonist, wild-type arterioles dilated in an expected manner (9.8 ± 0.7%), whereas A2A receptor knockout vessels had minimal response.

Conclusions

The results of the in vivo and in vitro studies in wild-type and A2A receptor knockout mice support the authors' hypothesis that hypercarbic vasodilation does not involve an adenosine A2A receptor–related mechanism.