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

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.