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Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed.
Eur J Pharmacol. 2001 Sep 21; 427(3):251-62.EJ

Abstract

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.

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Authors+Show Affiliations

Mendizábal VE
Instituto de Investigaciones Farmacológicas (ININFA-CONICET), Junín 956, 5 degrees Piso 1113, Buenos Aires, Argentina. vmendiz@huemul.ffyb.uba.ar
Orliac ML
No affiliation info available
Adler-Graschinsky E
No affiliation info available

MeSH

AnimalsArachidonic AcidsCannabinoid Receptor ModulatorsCapsaicinDose-Response Relationship, DrugDrug SynergismEndocannabinoidsEnzyme InhibitorsGuanylate CyclaseIn Vitro TechniquesIndolesMaleMesenteric ArteriesMorpholinesNG-Nitroarginine Methyl EsterNitric Oxide SynthaseNorepinephrineOxadiazolesPhenylmethylsulfonyl FluoridePolyunsaturated AlkamidesPyrazolesQuinoxalinesRatsRats, WistarTime FactorsVasoconstrictionVasoconstrictor Agents

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11567656

Citation

Mendizábal, V E., et al. "Long-term Inhibition of Nitric Oxide Synthase Potentiates Effects of Anandamide in the Rat Mesenteric Bed." European Journal of Pharmacology, vol. 427, no. 3, 2001, pp. 251-62.
Mendizábal VE, Orliac ML, Adler-Graschinsky E. Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed. Eur J Pharmacol. 2001;427(3):251-62.
Mendizábal, V. E., Orliac, M. L., & Adler-Graschinsky, E. (2001). Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed. European Journal of Pharmacology, 427(3), 251-62.
Mendizábal VE, Orliac ML, Adler-Graschinsky E. Long-term Inhibition of Nitric Oxide Synthase Potentiates Effects of Anandamide in the Rat Mesenteric Bed. Eur J Pharmacol. 2001 Sep 21;427(3):251-62. PubMed PMID: 11567656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed. AU - Mendizábal,V E, AU - Orliac,M L, AU - Adler-Graschinsky,E, PY - 2001/9/25/pubmed PY - 2001/11/3/medline PY - 2001/9/25/entrez SP - 251 EP - 62 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 427 IS - 3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/11567656/Long_term_inhibition_of_nitric_oxide_synthase_potentiates_effects_of_anandamide_in_the_rat_mesenteric_bed_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014299901012729 DB - PRIME DP - Unbound Medicine ER -