Ve. Mendizabal et al., Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed, EUR J PHARM, 427(3), 2001, pp. 251-262
In rat isolated mesenteric beds, anandamide induced a concentration-depende
nt reduction (0.01-50 muM) of the contractile responses elicited by bolus a
dministration of noradrenaline. The anandamide-induced reductions of noradr
enaline responses were unmodified by the in vitro exposure to the nitric ox
ide synthase (NOS) inhibitor, 100 muM 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 ra
ts made hypertensive by aortic coarctation. In mesenteric, beds isolated fr
om either untreated or in vivo L-NAME treated rats, concentration-response
curves to anandamide were significantly attenuated by the non-selective Kchannel blocker tetraethylammonium (TEA) but were not modified by either en
dothelium removal, or the soluble guanylate cyclase inhibitor 1H-[1,2,4] ox
adiazolo [4,3-a] quinoxalin-1-one (ODQ) or the cannabinoid receptor antagon
ists 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl] (4-methoxyph
enyl) methanone (AM630) and 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methy
l-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281). On the other hand, the
vanilloid receptor agonist (E)-N-[4-hydroxy-3-methoxyphenyl)methyl]-8-meth
yl-6-nonenamide (capsaicin) induced a concentration-dependent inhibition of
noradrenaline-induced vasoconstriction, and the vanilloid receptor antagon
ist N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benza
zepine-2-carbothioamide (capsazepine) caused a significant reduction of ana
ndamide-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-NA
ME treated rats. Moreover, in mesenteric beds from untreated but not from L
-NAME treated rats, the effects of anandamide were significantly potentiate
d by the inhibitor of endocannabinoid degradation, 200 muM phenylmethylsulp
honyl fluoride (PMSF), and by the inhibitor of anandamide uptake, 5 muM (al
l Z)-N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide (AM404). It is conclu
ded that long-term inhibition of NOS potentiates anandamide-induced relaxat
ions probably through changes in either endocannabinoid metabolism or uptak
e. A possible compensatory role for endocannabinoids in vascular function i
n situations in which nitric oxide (NO) synthesis is long-term impaired ari
ses from the present results. (C) 2001 Elsevier Science B.V. All rights res
erved.