Cannabinoid Receptor CB1 Subtype And Opioid Receptor δ Subtype Participate In The Development Of Vascular Hyporeactivity Resulting From Hemorrhagic Shock

Objective To explore whether cannabinoid receptor CB1 subtype (CB1R) and opioid receptorδsubtype (OPR-δ) were involved in the development of vascular hyporeactivity in rats suffering from hemorrhagic shock.Methods Forty-eight male SD rats were randomly divided into two groups (n=24 for each group): sham-operated (Sham) and hemorrhagic shock (HS) groups. Hemorrhagic shock was induced by exsanguination . The mean arterial pressure (MAP) was reduced to and stabilized at 25±5 mmHg for 2 h. The vascular reactivity was determined by measuring different doses of norepinephrine (2, 4, 6, 8μg/kg, 3ml/kg/hr, i.v.)-induced MAP change. Furthermore, CB1R and OPR-δexpressions in aorta and superior mesenteric artery (SMA) were determined by RT-PCR, immunohistochemistry and Western blotting in parallel experiments. In addition, rats were treated with antagonists of CB1R or OPR-δduring hemorrhagic shock, and corresponding vascular hyporeactivity and survival rates were determined.Results 1. Vascular hyporeactivity was developed in all animals suffering from hemorrhagic shock.2. The expression of CB1R in aorta and 2–3 branches of the SMA was significantly higher in the HS rats with vascular hyporeactivity that in Sham group both at mRNA and protein levels. Similar change was observed for OPR-δexpression.3. NE-induced MAP change was 4.31±0.36mmHg in HS rats treated with saline, while CB1R antagonist (SR141716A or AM251) restored it to 41.75±4.08 mmHg and 44.78±1.80 mmHg (P<0.01), and OPR antagonist (naloxone) raised it to 20.66±1.13 mmHg (P<0.01). Four-hour survival rate was enhanced by the three reagents as well. AM251 raised it by 30 %, which is significantly discrepant compared to saline treatment (P <0.05). However, SR141716A raised the survival rate by 20% and naloxone raised that by 15%, but with no statistically significant difference compared to saline treatment. Conclusions CB1R and OPR-δmediate (at least partially) vascular hyporeactivity during hemorrhagic shock. Consequently, antagonists of CB1R and OPR-δmight be promising therapeutic reagents treating patients with traumatic or hemorrhagic shock.