Long-Term Effects of the Adenosine Kinase Inhibitor GP-515 on Hepatic Microcirculation Following Hemorrhagic Shock

Abstract

Background: Microcirculatory perfusion failure, known as the “no-reflow phenomenon”, often develops within a few days after ischemia-reperfusion injury and can be a severe problem following resuscitation. Investigations with the adenosine kinase inhibitor GP-515 have shown beneficial protective effects on tissue. We investigated GP-515 in a long-term intravital microscopy rat model of hemorrhagic shock in order to evaluate its potential usage in prevention of multi-organ failure (MOF).

Material and Methods: Rats were randomly assigned to one of two shock groups that underwent microscopy after either 2 or 5 days, or to the control group that did not receive shock. After 90 min of hypotension, shock rats received GP-515 (0.25 mg/kg) or saline in a randomized and blinded manner, followed by 3 h of resuscitation. Intravital microscopy was performed after 2 or 5 days.

Results: After 2 days, sinusoidal blood flow was significantly improved by GP-515 (40,833 ± 2,499 μm³/s vs. 30,821 ± 3,332 μm³/s; p < 0.05 vs. placebo). Mean sinusoidal diameter was significantly increased in the GP-515 group after 2 days compared with the placebo group (12.08 ± 0.08 μm vs. 10.9 ± 0.08 μm; p < 0.05). After 5 days, the diameters were normalized in all groups. Perfusion index, indicating the proportion of perfused sinusoids to all investigated sinusoids, significantly increased in the GP-515 group (91.5 ± 1.5% compared with the placebo group 83.4 ± 1.8%; p < 0.05) after 2 days.

Conclusion: Systemic administration of GP-515 after shock results in a significant improvement of the microcirculation, which might have a long-lasting beneficial effect.