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The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication

A. T. Chaytor, P. E. M. Martin *, W. H. Evans *, M. D. Randall ¹ and T. M. Griffith

1. We have shown that the endocannabinoid anandamide and its stable analogue methanandamide relax rings of rabbit superior mesenteric artery through endothelium-dependent and -independent mechanisms that are unaffected by blockade of NO synthase and cyclooxygenase.

2. The endothelium-dependent component of the responses was attenuated by the gap junction inhibitor 18-glycyrrhetinic acid (18-GA; 50 µM), and a synthetic connexin-mimetic peptide homologous to the extracellular Gap 27 sequence of connexin 43 (⁴³Gap 27, SRPTEKTIFII; 300 µM). By contrast, the corresponding connexin 40 peptide (⁴⁰Gap 27, SRPTEKNVFIV) was inactive.

3. The cannabinoid CB₁ receptor antagonist SR141716A (10 µM) also attenuated endothelium-dependent relaxations but this inhibition was not observed with the CB₁ receptor antagonist LY320135 (10 µM). Furthermore, SR141716A mimicked the effects of ⁴³Gap 27 peptide in blocking Lucifer Yellow dye transfer between coupled COS-7 cells (a monkey fibroblast cell line), whereas LY320135 was without effect, thus suggesting that the action of SR141716A was directly attributable to effects on gap junctions.

4. The endothelium-dependent component of cannabinoid-induced relaxation was also attenuated by AM404 (10 µM), an inhibitor of the high-affinity anandamide transporter, which was without effect on dye transfer.

5. Taken together, the findings suggest that cannabinoids derived from arachidonic acid gain access to the endothelial cytosol via a transporter mechanism and subsequently stimulate relaxation by promoting diffusion of an to adjacent smooth muscle cells via gap junctions.

6. Relaxations of endothelium-denuded preparations to anandamide and methanandamide were unaffected by ⁴³Gap 27 peptide, 18-GA, SR141716A, AM404 and indomethacin and their genesis remains to be established.

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