Cannabinoid agonists induce relaxation in the bovine ophthalmic artery: evidences for CB1 receptors, nitric oxide and potassium channels

Glaucoma pathophysiology appears to involve vascular deficits, which may contribute to initiation and progression of the disease. 2 Anandamide, the endogenous cannabinoid ligand, and WIN55212-2, a synthetic cannabinoid agonist, are able to evoke concentration-dependent relaxations in bovine ophthalmic artery rings, precontracted with 5-hydroxytryptamine (5-HT) (1 mM). Endothelium removal reduces cannabinoid agonist potency and efficacy. 3 The selective cannabinoid 1 (CB1) receptor antagonists SR141716A (100 nM) and AM251 (100 nM) cause a shift to the right in the concentration–response curves to anandamide and WIN55212-2 in arterial rings both in the presence and in the absence of endothelium. 4 In endothelium-intact arteries, the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA, 300 mM), completely blocked the anandamide- and WIN55212-2-relaxant responses; by contrast, the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP, 100 mM) induced an increase in vasorelaxant responses to cannabinoid agonists. 5 Relaxations to anandamide and WIN55212-2 were inhibited by iberiotoxin (IbTX, 200 nM), a blocker of large conductance, Ca2þ-activated Kþ channel (BKCa), and by 4-aminopyridine (4-AP; 1mM), a blocker of delayed rectifier K+ channel, whereas the blockade of KATP channels by glibenclamide (5 mM) and of small conductance Ca2+-activated K+ channels (SKCa) by apamin (100 nM) did not produce any effects. 6 These data suggest that anandamide and WIN55212-2 relax the bovine ophthalmic artery by involving CB1 the cannabinoid receptor-sensitive pathway. In endothelium-intact arteries, relaxation occurs through activation of nitric oxide synthase cyclic GMP and Ca2+-activated K+ channels. They also cause endothelium-independent relaxation by involving potassium channel opening.