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

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.

• Authors: Rong Zhou, Feng Chen, Qiang Li, De-yao Hu, Liang-ming Liu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 31 Issue 4 Pg. 413-20 (Apr 2010) ISSN: 1745-7254 [Electronic] United States
• PMID: 20348945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Large-Conductance Calcium-Activated Potassium Channels
• Receptor, Adenosine A3
• Ryanodine Receptor Calcium Release Channel
• Vasoconstrictor Agents
• Calcium
• Norepinephrine

Topics

• Animals
• Aorta, Abdominal (cytology)
• Calcium (metabolism)
• Cell Hypoxia (drug effects)
• Cells, Cultured
• Gene Expression
• Large-Conductance Calcium-Activated Potassium Channels (metabolism)
• Muscle, Smooth, Vascular (cytology, drug effects)
• Norepinephrine (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptor, Adenosine A3 (genetics, metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Shock, Hemorrhagic (metabolism)
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)