Stimulation of the adenosine A3 receptor reverses vascular hyporeactivity after hemorrhagic shock in rats

• Published in: Acta pharmacologica Sinica 2010-04, Vol.31 (4), p.413-420
• Main Authors: Zhou, Rong, Chen, Feng, Li, Qiang, Hu, De-yao, Liu, Liang-ming
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Abdominal - cytology; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Cell Hypoxia - drug effects; Cells, Cultured; Gene Expression; Immunology; Internal Medicine; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Medical Microbiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Norepinephrine - pharmacology; Original; original-article; Pharmacology/Toxicology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Adenosine A3 - genetics; Receptor, Adenosine A3 - metabolism; Ryanodine Receptor Calcium Release Channel - metabolism; Shock, Hemorrhagic - metabolism; Vaccine; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology; 反应性; 失血性休克
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2010.18

Aim： To investigate whether adenosine A3 receptors （A3AR） stimulation restore vascular reactivity after hemorrhagic shock through a ryanodine receptor （RyR）-mediated and large conductance calcium-activated potassium （BKCa） channel-dependent pathway. Methods： Rat hemorrhagic shock model （40 mmHg） and vascular smooth muscle cell （VSMC） hypoxic model were used. The expression of A3AR was determined by Western blot and RT-PCR. The effect of A3AR stimulation on RyR-mediated Ca^2＋ release in VSMCs was analyzed by the Fura-3/AM loading Ca^2＋ imaging. The modulation of vascular reactivity to norepinephrine （NE） by A3AR stimulation was monitored by an isolated organ tension instrument. Results： Decrease of A3AR expression is consistent with the loss of vasoreactivity to NE in hemorrhagic shock rats. The stimulation of A3AR with a selective agonist, IB-MECA, could partly but significantly restore the vasoreactivity in the rats, and this restorative effect could be counteracted by MRS1523, a selective A3AR antagonist. In hypoxic VSMCs, RyR activation by caffeine significantly evoked the rise of [Ca^2＋] compared with the control cells, a phenomenon closely associated with the development of vascular hyporeactivity in hemorrhagic shock rats. The stimulation of A3AR with IB-MECA significantly blocked this over activation of RyR-mediated Ca^2＋ release. RyR activation by caffeine and BKCa channel activation by NS1619 attenuated the restoration of vasoreactivity to NE resulting from A3AR stimulation by IB-MECA after hemorrhagic shock; this attenuation effect could be antagonized by a selective BKCa channel blocker. Conclusion： These findings suggest that A3AR is involved in the modulation of vasoreactivity after hemorrhagic shock and that stimulation of A3AR can restore the decreased vasoreactivity to NE through a RyR-mediated, BKCa channel-dependent signal pathway.