To test the hypothesis that mechanically stretched arteries relax to endothelium-derived vasodilators, we challenged endothelium-intact dog femoral artery rings stretched from 1 to 16 g total initial tension (active force and passive elastic) with 106 M acetylcholine (ACh), an endothelium-dependent dilator. The relaxation to 106 M sodium nitroprusside (SNP), an endothelium-independent dilator, increased with the total initial tension. The relaxation to ACh averaged approximately 65% of the relaxation to SNP at total initial tensions of 4 to 16 g. To determine the nature of the endothelial-derived products involved, we compared the ACh-induced relaxation of stretched rings (6.5 ± 0.2 g total initial tension) with rings chemically contracted with phenylephrine (Phe, 107 to 105 M) (6.5 ± 0.3 g total initial tension). ACh-induced relaxation was evaluated before and after the inhibition of the synthesis of eicosanoids [cyclooxygenase (105 M indomethacin) and lipoxygenase (105 M nordihydroguariaretic acid)] and nitric oxide [nitric oxide synthase (105 M Nw-nitro-L-arginine)]. The contribution of endothelium-derived hyperpolarizing factor (EDHF) was identified by blocking calcium-activated potassium channels (108 M iberiotoxin). SNP (106 M) relaxed stretched rings by 1.7 ± 0.1 g and chemically-activated rings by 4.8 ± 0.2 g. ACh relaxed stretched rings to 73 ± 3% of the SNP relaxation and this was only attenuated in the presence of iberiotoxin. ACh relaxed Phe-activated rings to 60 ± 3% of the SNP relaxation. This relaxation was attenuated by inhibition of the synthesis of nitric oxide and (or) eicosanoids. Therefore, ACh relaxed stretched rings through the release of EDHF whereas the relaxation of chemically activated rings to ACh involved multiple endothelium-derived vasodilators.Key words: endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF), arachidonic acid metabolites.
Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase.
