The diacylglycerol lipase inhibitor RHC-80267 potentiates the relaxation to acetylcholine in rat mesenteric artery by anti-cholinesterase action.
The diacylglycerol lipase inhibitor 1,6-bis(cyclohexyloximinocarbonylamino) hexane (RHC-80267) was tested for its effect on acetylcholine-evoked relaxation in rat mesenteric artery. In artery contracted with either noradrenaline or KCl, RHC-80267 (0.1-10 muM) potentiated the relaxation evoked by acetylcholine. The effect of RHC-80267 was not affected by nitric oxide synthase inhibition or by inhibitors of protein kinase C or of phospholipase A(2). The diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol did not change the relaxation to acetylcholine. RHC-80267 did not affect the relaxation evoked by carbachol, by the nitric oxide donor SNAP (S-nitroso-N-acetylpenicillamine) or by the K(+) channel opener cromakalim. Neostigmine, a cholinesterase inhibitor, produced the same effect as RHC-80267 on acetylcholine-evoked relaxation. When tested on cholinesterase in brain homogenate, RHC-80267 concentration-dependently inhibited cholinesterase activity with an IC(50) of 4 muM. These results indicate that the potentiation of acetylcholine-evoked responses by RHC-80267 in rat mesenteric artery is caused by the inhibition of the cholinesterase activity in the vascular wall.
Ghisdal
Philippe
P
Laboratoire de Pharmacologie expérimentale-Université Catholique de Louvain- UCL 5410- Avenue Hippocrate, 54- B 1200 Bruxelles, Belgium.
Vandenberg
Greet
G
Hamaide
Marie-Christine
MC
Wibo
Maurice
M
Morel
Nicole
N
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D019806:Cromakalim / Q000494:pharmacology; D003512:Cyclohexanones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D011921:Rats, Inbred WKY; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D002800:Cholinesterase Inhibitors; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C061465:calphostin complex; C067410:endothelium-dependent hyperpolarization factor; D019806:Cromakalim; D019335:Nitroarginine; D009569:Nitric Oxide; D009388:Neostigmine; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D010741:Phospholipases A; D008071:Lipoprotein Lipase; D002802:Cholinesterases; D010396:Penicillamine; D000109:Acetylcholine; D009638:Norepinephrine