CP55, 940 and anandamide inhibit sympathetic nerve-mediated responses in the rat perfused mesenteric vascular bed under raised tone conditions

Poungrat Pakdeechote, Vera Ralevic & William R. Dunn. Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom.

Cannabinoids have been reported to exert an inhibitory action on sympathetic neurogenic contraction in rat isolated mesenteric vascular beds under normal conditions (Ralevic & Kendall, 2002). The present study assessed whether CP55,940, a cannabinoid CB1 receptor agonist, and anandamide, an endogenous cannabinoid, influenced contraction evoked by nerve stimulation in the rat perfused mesenteric vascular bed after raising tone with U46619, to approximate more closely physiological perfusion pressure.

Male rat isolated mesenteric vascular beds were perfused with warmed, oxygenated Kreb’s solution and pretreated with capsaicin (1 µM) to defunctionalise sensory nerves. Electrical field stimulation (EFS; 5-40 Hz, 1 ms, 90V, 30s) was performed under basal conditions and after raising baseline perfusion pressure with U46619. The effects of CP55,940 ( 1 µM) or anandamide (1 µM) on responses to EFS were examined under raised tone conditions. In some experiments either LY320135 (1 µM), a cannabinoid CB 1 receptor antagonist, or SR144528 ( 1 µM) , a cannabinoid CB2 receptor antagonist were presented to determine whether they reversed the effect of the CB1/CB2 receptor agonists.

U46619 significantly increased perfusion pressure from 14 ± 2 mmHg to 62 ± 2 mmHg (mean + S.E.M.(P<0.05) (n = 5) and increased contractile responses to EFS (e.g. at 30 Hz basal 53 ± 4, U46619 145 ± 14 mmHg (P<0.05) (n = 5)). CP55,940 inhibited the contractile responses to sympathetic nerve stimulation under these conditions e.g. at 30 Hz (from 145 ± 14 to 60 ± 5 mmHg) (P < 0.05, n = 5). This inhibitory effect of CP55940 was not reversed by either LY320135 or SR144528, or a combination of LY320135 and SR144528. Anandamide also inhibited the contractile response to sympathetic nerve stimulation, eg. at 30 Hz (from 76 ± 8 to 50 ± 10 mmHg) (P < 0.05, n = 6). Anandamide had no significant effect on contractile responses in the presence of LY320135 (n = 6). These data indicate, that under U46619 raised tone conditions, CP55,940 can modulate sympathetic neurotransmission by decreasing the neurogenic response in the rat perfused mesenteric vascular bed. The inhibitory actions of CP55,940 appear to be mediated by a non-CB1/CB2 receptor. By contrast, anandamide had an inhibitory action on sympathetic neurotransmission which was mediated by a CB1 -like receptor.

Ralevic, V. & Kendall, D.A. (2002). Eur. J. Pharmacol, 444: 171-181.