Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed.
In rat isolated mesenteric beds, anandamide induced a concentration-dependent reduction (0.01-50 microM) of the contractile responses elicited by bolus administration of noradrenaline. The anandamide-induced reductions of noradrenaline responses were unmodified by the in vitro exposure to the nitric oxide synthase (NOS) inhibitor, 100 microM L-N(G)-nitro-L-arginine methyl ester (L-NAME), whereas they were significantly potentiated after the long-term in vivo administration of L-NAME (70 mg/kg/day during 4 weeks). Responses to anandamide were not potentiated and even reduced in mesenteric beds from rats made hypertensive by aortic coarctation. In mesenteric beds isolated from either untreated or in vivo L-NAME treated rats, concentration-response curves to anandamide were significantly attenuated by the non-selective K+ channel blocker tetraethylammonium (TEA) but were not modified by either endothelium removal, or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) or the cannabinoid receptor antagonists 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl] (4-methoxyphenyl) methanone (AM630) and 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281). On the other hand, the vanilloid receptor agonist (E)-N-[4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonenamide (capsaicin) induced a concentration-dependent inhibition of noradrenaline-induced vasoconstriction, and the vanilloid receptor antagonist N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine) caused a significant reduction of anandamide-induced responses in mesenteric beds isolated from both control and chronic L-NAME treated rats. The non-metabolizable analogue of anandamide, methanandamide, produced higher reductions of noradrenaline responses than anandamide in mesenteric beds isolated from controls but not from the L-NAME treated rats. Moreover, in mesenteric beds from untreated but not from L-NAME treated rats, the effects of anandamide were significantly potentiated by the inhibitor of endocannabinoid degradation, 200 microM phenylmethylsulphonyl fluoride (PMSF), and by the inhibitor of anandamide uptake, 5 microM (all Z)-N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide (AM404). It is concluded that long-term inhibition of NOS potentiates anandamide-induced relaxations probably through changes in either endocannabinoid metabolism or uptake. A possible compensatory role for endocannabinoids in vascular function in situations in which nitric oxide (NO) synthesis is long-term impaired arises from the present results.
Mendizábal
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Instituto de Investigaciones Farmacológicas (ININFA-CONICET), Junín 956, 5 degrees Piso 1113, Buenos Aires, Argentina. vmendiz@huemul.ffyb.uba.ar
Orliac
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Adler-Graschinsky
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D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007211:Indoles; D009025:Morpholines; D010069:Oxadiazoles; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011810:Quinoxalines; D014662:Vasoconstrictor Agents; C088155:methanandamide; D010664:Phenylmethylsulfonyl Fluoride; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D002211:Capsaicin; C109925:AM 281; C094023:iodopravadoline; C078814:anandamide; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; C107594:N-(4-hydroxyphenyl)arachidonylamide