Two distinct pathways account for EDHF-dependent dilatation in the gracilis artery of dyslipidaemic hApoB+/+ mice.

1 A universal endothelium-derived hyperpolarising factor (EDHF--non-NO/non-PGI(2)) has not been identified. EDHF, however, is essential for the physiological control of resistance artery tone. The impact of dyslipidaemia (DL), a risk factor for cardiovascular diseases, on the nature and the efficacy of EDHF has not been evaluated yet. 2 Pressurised (80 mmHg) gracilis arterial segments isolated from mice expressing the human apoB-100 and C57Bl/6 wild-type (WT) mice were used. EDHF-dependent dilatations to acetylcholine (ACh) were measured in the presence of L-NNA (100 microM, NOS inhibitor) and indomethacin (10 microM, COX inhibitor). 3 Maximal EDHF-induced dilatations were increased in DL when compared to WT (95+/-2 versus 86+/-4% in WT; P<0.05). Combination of apamin and charybdotoxin strongly reduced (P<0.05) ACh-induced dilatation in WT (22+/-4%) and DL (25+/-5%). 4 Combined addition of barium (Ba(2+)) and ouabain abolished EDHF-induced dilatations in WT arteries (13+/-3%; P<0.05). In vessels isolated from DL mice, however, only the addition of 14,15-EEZE (a 14,15-EET antagonist) to Ba(2+) and ouabain prevented EDHF-induced dilatations (5+/-3% compared to 54+/-11% in the presence of combined Ba(2+) and ouabain; P<0.05). 5 Our data suggest that EDHF-mediated dilatation depends on the opening of endothelial SK(Ca) and IK(Ca) channels. This is associated with the opening of K(ir) channels and activation of the Na(+)/K(+)-ATPase pump on smooth muscle cells leading to dilatation. In arteries from DL mice, a cytochrome P450 metabolite likely to be 14,15-EET equally contributes to the dilatory action of ACh. The early increased efficacy of EDHF in arteries isolated from DL mice may originate from the duplication of the EDHF pathways.