Acetylcholine-induced relaxation of peripheral arteries isolated from micelacking endothelial nitric oxide synthase

1 Acetycholine-mediated relaxations in phenylephrine-contracted aortas, fem oral and mesenteric resistance arteries were studied in vessels from endoth elial nitric oxide synthase knock-out (eNOS -/-) and the corresponding wild -type strain (eNOS +/+) C57BL6/SV19 mice. 2 Aortas from eNOS (+/+) mice relaxed to acetylcholine in an endothelium-de pendent N-G-nitro-L-arginine (L-NOARG) sensitive manner. Aortas from eNOS ( -/-) mice did not relax to acetylcholine but demonstrated enhanced sensitiv ity to both authentic NO and sodium nitroprusside. 3 Relaxation to acetylcholine in femoral arteries was partially inhibited b y L-NOARG in vessels from eNOS (+/+) mice, but relaxation in eNOS (-/-) mic e was insensitive to a combination of L-NOARG and indomethacin and the guan ylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). T he L-NOARG/ODQ/indomethacin-insensitive relaxation to acetylcholine in femo ral arteries was inhibited in the presence of elevated (30 mM) extracellula r KCl. 4 In mesenteric resistance vessels from eNOS (+/+) mice, the acetylcholine- mediated relaxation response was completely inhibited by a combination of i ndomethacin and L-NOARG or by 30 mM KCI alone. In contrast, in mesenteric a rteries from eNOS (-/-) mice, the acetylcholine-relaxation response was ins ensitive to a combination of L-NOARG and indomethacin, but was inhibited in the presence of 30 mM KCl. 5 These data indicate arteries from eNOS (-/-) mice demonstrate a supersens itivity to exogenous NO, and that acetylcholine-induced vasorelaxation of f emoral and mesenteric vessels from eNOS (-/-) mice is mediated by an endoth elium-derived factor that has properties of an EDHF but is neither NO nor p rostacyclin. Furthermore, in mesenteric vessels, there is an upregulation o f the role of EDHF in the absence of NO.