Role of Nitric Oxide, Cyclic Nucleotides, and the Activation of ATP-Sensitive K+ Channels in the Contribution of Adenosine to Hypoxia-Induced Pial Artery Dilation

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Abstract
Previously, it had been observed that nitric oxide (NO) contributes to hypoxia-induced pial artery dilation in the newborn pig. Additionally, it was also noted that activation of ATP-sensitive K+ channels (KATP) contribute to cGMP-mediated as well as to hypoxia-induced pial dilation. Although somewhat controversial, adenosine is also thought to contribute to hypoxic cerebrovasodilation. The present study was designed to investigate the role of NO, cyclic nucleotides, and activation of KATP channels in the elicitation of adenosine's vascular response and relate these mechanisms to the contribution of adenosine to hypoxia-induced pial artery dilation. The closed cranial window technique was used to measure pial diameter in newborn pigs. Hypoxia-induced artery dilation was attenuated during moderate (PaO2 ≈ 35 mm Hg) and severe hypoxia (PaO2 ≈ 25 mm Hg) by the adenosine receptor antagonist 8-phenyltheophylline (8-PT) (10–5 M) (26 ± 2 vs. 19 ± 2 and 34 ± 2 vs. 22 ± 2% for moderate and severe hypoxia in the absence vs. presence of 8-PT, respectively). This concentration of 8-PT blocked pial dilation in response to adenosine (8 ± 2, 16 ± 2, and 23 ± 2 vs. 2 ± 2, 4 ± 2, and 6 ± 2% for 10–8, 10–6, and 10–4 M adenosine before and after 8-PT, respectively). Similar data were also obtained using adenosine deaminase as a probe for the role of adenosine in hypoxic pial dilation. Adenosine-induced dilation was associated with increased CSF cGMP concentration (390 ± 11 and 811 ± 119 fmol/ml for control and 10–4 M adenosine, respectively). The NO synthase inhibitor, L-NNA, and the cGMP antagonist, Rp 8-bromo cGMPs, blunted adenosine-induced pial dilation (8 ± 1, 14 ± 1, and 20 ± 3 vs. 3 ± 1, 5 ± 1, and 8 ± 3% for 10–8, 10–6, and 10–4 M adenosine before and after L-NNA, respectively). Adenosine dilation was also blunted by glibenclamide, a KATP antagonist (9 ± 2, 14 ± 3, 21 ± 4 vs. 4 ± 1, 8 ± 2, and 11 ± 2% for 10–8, 10–6, and 10–4 M adenosine before and after glibenclamide, respectively). Finally, it was also observed that adenosine-induced dilation was associated with increased CSF cAMP concentration and the cAMP antagonist, Rp 8-bromo cAMPs, blunted adenosine pial dilation. These data show that adenosine contributes to hypoxic pial dilation. These data also show that NO, cGMP, cAMP, and activation of KATP channels all contribute to adenosine induced pial dilation. Finally, these data suggest that adenosine contributes to hypoxia-induced pial artery dilation via cAMP and activation of KATP channels by NO and cGMP.

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