Effects Of The Novel Cannabinoid Peptide Ligands-hemopressin And Its Related Peptides On Gastrointestinal Transit In Mice And Blood Pressure Regulation In Rats

Cannabinoid system involves in the regulation of many biological activities in vivo, and it has been suggested to play an important role on gastrointestinal transit and cardiovascular regulation. Recently, a kind of novel cannabinoid peptide ligands-hemopressin (Hpa) and its related peptides ((m)VD-Hpβ and (m)VD-Hpa, etc.) have been identified, and in vitro studies have shown that these peptide ligands selectively activated cannabinoid receptors and participated signal transduction. However, the pharmacological activities of these endocannabinoid peptide ligands are still unclear, especially there are few reports about the regulation activities in vivo of these peptide ligands. The present study was undertaken to investigate the effects of hemopressin and related peptide on the gastrointestinal transit and blood pressure regulation.To characterize the roles of intracerebroventricular (i.c.v) administration of (m)VD-Hpβ, (m)VD-Hpa and Hpa on the gastrointestinal transit, in vivo tests comprising upper gastrointestinal transit, colonic bead expulsion and whole gut transit were evaluated. The results showed that:(1) i.c.v. administration of (m)VD-Hpβ, (m)VD-Hpa, Hpa and WIN55212-2 (a lipoid cannabinoid agonist) induced dose-dependent decreases in upper gastrointestinal transit, which were completely blocked by CB1 receptor selective antagonist AM251, but not by CB2 receptor selective antagonist AM630; (2) i.c.v. administration of (m)VD-Hpβ, (m)VD-Hpa, Hpa and WIN55212-2 inhibited colonic bead expulsion, which were counteracted by pre-treatment with AM251, not by AM630; (3) i.c.v. administration of (m)VD-Hpβ, Hpa and WIN55212-2 at high doses reduced whole gut transit, which were also blocked by AM251, but not by AM630, while (m)VD-Hpa had no inhibitory effect on whole gut transit even at higher doses.In addition, we aslo investigated the intrathecal (i.t.) action of cannabinoid peptide agnosit (m)VD-Hpa on blood pressure and its involved mechanism in urethane-anesthetized rats. The results showed that:(1) i.t. injection of (m)VD-Hpa and WTN55212-2 caused dose-dependent decreases in mean arterial pressure (MAP) in anesthetized rats; (2) the hypotension of (m)VD-Hpa (i.t.) was not modified by the CB1 receptor selective antagonist AM251 (i.t.) or CB2 receptor selective antagonist AM630 (i.t.), but the hypotension of WIN55212-2 (i.t.) was almost completely prevented by i.t. administration of AM251, not by AM630; (3) pretreatment with the a-adrenoceptor antagonist phentolamine (i.v.) significantly reduced the spinal hypotension of (m)VD-Hpa and WIN55212-2, but neither the β-adrenoceptor antagonist propranolol (i.v.) nor the muscarinic receptor antagonist atropine (i.v.) affected their hypotension. In addition, L-NAME (i.v.), the inhibitor of nitric oxide (NO) synthase, significantly reduced WIN55212-2-induced hypotension, but had no effect on the hypotensive response induced by (m)VD-Hpa.Taken together, our study shows that intracerebroventricular (i.c.v) administration of (m)VD-HpP, (m)VD-Hpa and Hpa had inhibitory effects at many aspects on gastrointestinal transit. Furthermore, their inbibitiory effects were modified by CB1 receptor, not by CB2 receptor. In addition, i.t. administration of (m)VD-Hpa induced a decrease in MAP via a non-CB1, non-CB2 mechanism, but by a-adrenergic receptor regulation, The hypotension of (m)VD-Hpa at the spinal level was independent on systemic NO. Our study is the first report that the endocannabinoid peptide ligands Hpa and its related peptides involved in gastrointestinal transit and cardiovascular regulation, which is helpful to understand the biological functions of the novel endocannabinoid peptide ligands.