F. Perez-vizcaino et al., Vasodilator effects of sodium nitroprusside, levcromakalim and their combination in isolated rat aorta, BR J PHARM, 128(7), 1999, pp. 1419-1426
1 The endothelial modulation of the relaxant responses to the nitric oxide
(NO) donor sodium nitroprusside (SNP) and the K-ATP channel opener levcroma
kalim (LEM) and the interactions between these agents were analysed in isol
ated rat aorta.
2 LEM-induced relaxation was unchanged by endothelium removal or by the pre
sence of L-NAME (10(-4) M) or ODQ (10(-6) M). In contrast, in KCl- (25 mM),
but not in noradrenaline- (NA, 10(-6) M) contracted arteries, SNP-induced
relaxation was augmented by endothelium removal but not by L-NAME, indometh
acin, glibenclamide nor charybdotoxin plus apamin.
3 The isobolographic analysis of the interactions between exogenously activ
ated KATP channels and cyclic GMP using mixtures of SNP and LEM revealed th
at there were no interactions between both drugs at the proportions at whic
h both drugs were active. However, the points for the SNP:LEM mixtures in p
roportions 10:1 and 1:10,000 (i.e. at concentrations at which LEM and SNP w
ere inactive, respectively) fell significantly above the line of additivity
indicating that there were negative interactions between both drugs at the
se selected proportions (about 5- and 2 fold inhibition, respectively). The
former interaction was sensitive to glibenclamide, whereas the latter was
insensitive ODQ. The magnitude of the 10:1 SNP:LEM interaction was smaller
in endothelium-intact arteries and was absent in arteries stimulated by NA.
4 In conclusion, the relaxations induced by LEM and SNP were additive. Howe
ver, the presence of endothelium and low concentrations of LEM inhibited SN
P-induced relaxation. Both inhibitory effects were not additive and were on
ly observed in KCl- and not in NA-contracted aortae.