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

  • Acta Pharmacol Sin. 2010 Apr;31(4):413-20. doi: 10.1038/aps.2010.18.
Rong Zhou  1 ,  Feng Chen ,  Qiang Li ,  De-yao Hu ,  Liang-ming Liu
Affiliations
  • 1. State Key Laboratory of Trauma, Burns and Combined Injury, 2nd Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China. [email protected]
PMID: 20348945 DOI: 10.1038/aps.2010.18
Abstract

Aim: To investigate whether adenosine A(3) receptors (A(3)AR) stimulation restore vascular reactivity after hemorrhagic shock through a ryanodine receptor (RyR)-mediated and large conductance calcium-activated potassium (BK(CA)) channel-dependent pathway.

Methods: Rat hemorrhagic shock model (40 mmHg) and vascular smooth muscle cell (VSMC) hypoxic model were used. The expression of A(3)AR was determined by Western blot and RT-PCR. The effect of A(3)AR 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 A(3)AR stimulation was monitored by an isolated organ tension instrument.

Results: Decrease of A(3)AR expression is consistent with the loss of vasoreactivity to NE in hemorrhagic shock rats. The stimulation of A(3)AR 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 A(3)AR 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 A(3)AR with IB-MECA significantly blocked this over activation of RyR-mediated CA(2+) release. RyR activation by caffeine and BK(CA) channel activation by NS1619 attenuated the restoration of vasoreactivity to NE resulting from A(3)AR stimulation by IB-MECA after hemorrhagic shock; this attenuation effect could be antagonized by a selective BK(CA) channel blocker.

Conclusion: These findings suggest that A(3)AR is involved in the modulation of vasoreactivity after hemorrhagic shock and that stimulation of A(3)AR can restore the decreased vasoreactivity to NE through a RyR-mediated, BK(CA) channel-dependent signal pathway.

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