Vasodilator effects of sodium nitroprusside, levcromakalim and their combination in isolated rat aorta

The endothelial modulation of the relaxant responses to the nitric oxide (NO) donor sodium nitroprusside (SNP) and the KATP channel opener levcromakalim (LEM) and the interactions between these agents were analysed in isolated rat aorta. LEM‐induced relaxation was unchanged by endothelium removal or by the presence 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, indomethacin, glibenclamide nor charybdotoxin plus apamin. The isobolographic analysis of the interactions between exogenously activated KATP channels and cyclic GMP using mixtures of SNP and LEM revealed that there were no interactions between both drugs at the proportions at which both drugs were active. However, the points for the SNP : LEM mixtures in proportions 10 : 1 and 1 : 10,000 (i.e. at concentrations at which LEM and SNP were inactive, respectively) fell significantly above the line of additivity indicating that there were negative interactions between both drugs at these 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. In conclusion, the relaxations induced by LEM and SNP were additive. However, the presence of endothelium and low concentrations of LEM inhibited SNP‐induced relaxation. Both inhibitory effects were not additive and were only observed in KCl‐ and not in NA‐contracted aortae. British Journal of Pharmacology (1999) 128, 1419–1426; doi:10.1038/sj.bjp.0702924