An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide

Myogenic tone is an important determinant of vascular tone and blood flow i n small resistance arteries of certain vascular beds. The role of the endot helium in myogenic responses is unclear. We hypothesized that endothelium-d erived NO release modulates myogenic constriction in small resistance arter ies and that mesenteric small arteries from mice with targeted disruption o f the gene for endothelial NO synthase (eNOS) (knockout mice) demonstrate g reater myogenic tone than do wild-type mice. Third-order mesenteric arterie s (similar to 200 mum) were isolated and mounted in a pressure myograph. In ternal diameter was recorded over a pressure range of 10 to 80 mm Hg. Remov al of the endothelium significantly (P<0.05) enhanced the magnitude of myog enic constriction in wild-type mice. Similarly, pretreatment of arteries wi th N-G-nitro-L-arginine methyl ester (L-NAME; 300 <mu>mol/L) produced a com parable significant (P<0.05) increase in myogenic tone, whereas indomethaci n (5 <mu>mol/L) had no effect. eNOS knockout arteries also exhibited myogen ic constriction. Neither L-NAME nor indomethacin had any effect on myogenic tone in the arteries of eNOS knockout mice. However, blockade of potential endothelium-derived hyperpolarizing factor-like mechanisms via inhibition of K+ flux using either apamin (100 nmol/L) with charybdotoxin (100 nmol/L) , Ba2+ (30 mu mol/L) with ouabain (1 mmol/L), or 18 alpha -glycyrrhetinic a cid (100 mu mol/L) significantly (P<0.01) enhanced myogenic constriction. T his study demonstrates that basal endothelium-derived NO modulates myogenic tone in mesenteric small arteries of wild-type mice. However, eNOS knockou t arteries display normal myogenic responsiveness despite the absence of ba sal NO activity. The data suggest that this compensatory effect is due to t he activity of an endothelium-derived hyperpolarizing factor to normalize v ascular tone.