B. Vanheel et J. Van De Voorde, Regional differences in anandamide- and methanandamide-induced membrane potential changes in rat mesenteric arteries, J PHARM EXP, 296(2), 2001, pp. 322-328
Citations number
27
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
The possibility that anandamide is an endothelium-derived hyperpolarizing f
actor was explored in the rat mesenteric vasculature by use of conventional
microelectrode techniques. In the main mesenteric artery, anandamide and i
ts more stable analog methanandamide hardly caused a measurable change in m
embrane potential of the smooth muscle cells, which promptly hyperpolarized
to EDHF liberated by acetylcholine. Inhibition of endogenous anandamide br
eakdown by phenylmethylsulfonyl fluoride did not increase membrane response
s to acetylcholine. The CB1 receptor antagonist SR141716 did not significan
tly influence EDHF-mediated hyperpolarization except at extremely high conc
entrations. Smooth muscle cells of third to fourth order branches of the me
senteric artery, which have a more negative resting membrane potential and
show smaller responses to acetylcholine, hyperpolarized by about 6 mV to bo
th anandamide and methanandamide, whereas another CB1 receptor agonist, WIN
55,212-2, had no effect. Mechanical endothelium removal or pre-exposure to
SR141716A did not affect anandamide- and methanandamide-induced hyperpolar
izations. However, in the presence of capsazepine, a selective vanilloid re
ceptor antagonist, these membrane potential changes were reversed to a smal
l depolarization, whereas EDHF-induced hyperpolarizations were not affected
. Pretreating small vessels with capsaicin, causing desensitization of vani
lloid receptors and/or depletion of sensory neurotransmitter, completely bl
ocked methanandamide-induced hyperpolarizations. These findings show that a
nandamide cannot be EDHF. In smooth muscle cells of small arteries, anandam
ide-induced changes in membrane potential are mediated by vanilloid recepto
rs on capsaicin-sensitive sensory nerves. The different membrane response t
o the cannabinoids between the main mesenteric artery and its daughter bran
ches might be explained by the different density of perivascular innervatio
n.