Ha. Peredo et E. Adler-graschinsky, Effects of eicosanoids and nitric oxide on the noradrenaline-induced contractions in the rat mesenteric bed, J AUT PHARM, 20(3), 2000, pp. 163-170
1 The effects of the inhibition of the metabolism of arachidonic acid (AA)
on the constrictor responses. to noradrenaline (NA) were studied in the rat
perfused mesenteric bed. The inhibitor of all the pathways of AA metabolis
m 10 muM eicosatetraynoic acid (ETYA), reduced the constrictor responses to
all the concentrations of NA assayed.
2 The constrictor responses to NA were also reduced by the cyclooxygenase (
COX) inhibitor, indomethacin (10 CIM), as well as by the lipoxygenase inhib
itor, nordihidroguaiaretic acid (1 muM: NDGA), whereas they were unmodified
by the cytochrome P450 monooxigenase inhibitors, clotrimazole (10 muM), me
tyrapone (10 muM) and proadifen (10 muM).
3 The reduction in NA contractility induced by indomethacin was reverted wi
th a decreasing order of potency by the thromboxane A(2) analogue, U-46619
> prostaglandin (PG) E-2 > PGF(2)alpha. The exposure of the mesenteric bed
to NA increased the production of PGF(2)alpha, whereas it did not modify th
e production of the remaining AA metabolites.
4 The increase in the NA-induced contractions caused by endothelium removal
, as well as by the inhibition of nitric oxide synthase (NOs) with N-G-nitr
o-L-arginine methyl ester (400 muM; L-NAME), was suppressed by indomethacin
but not by NDGA. These observations suggest that the lipoxygenase-derived
metabolites are formed in the endothelium, whereas the COX-derived metaboli
tes are formed in the vascular smooth muscle.
5 The TP receptor antagonist, SQ29548, did not modify the NA-induced contra
ctions, either in the presence or in the absence of the endothelium.
6 Contractions elicited by KCl (60-100 mM) were unmodified by the AA metabo
lism inhibitors, ETYA, NDGA and indomethacin.
7 In summary, these results show that metabolites of AA, through both the C
OX and the lipoxygenase pathways, are involved in the NA-induced contractio
ns in the rat mesenteric bed. The lipoxygenase metabolites are likely to be
formed in the vascular endothelium, whereas the COX metabolite, which coul
d be PGF(2)alpha, is apparently formed within the vascular smooth muscle.