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Contributions of endothelium-derived relaxing factors to control of hindlimb blood flow in the mouse in vivo

Department of Physiology, Monash University, Melbourne, Victoria, Australia

Submitted 17 January 2007 ; accepted in final form 24 April 2007

We determined the contributions of various endothelium-derived relaxing factors to control of basal vascular tone and endothelium-dependent vasodilation in the mouse hindlimb in vivo. Under anesthesia, catheters were placed in a carotid artery, jugular vein, and femoral artery (for local hindlimb circulation injections). Hindlimb blood flow (HBF) was measured by transit-time ultrasound flowmetry. N-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg plus 10 mg·kg^–1·h^–1), to block nitric oxide (NO) production, altered basal hemodynamics, increasing mean arterial pressure (30 ± 3%) and reducing HBF (–30 ± 12%). Basal hemodynamics were not significantly altered by indomethacin (10 mg·kg^–1·h^–1), charybdotoxin (ChTx, 3 x 10^–8 mol/l), apamin (2.5 x 10^–7 mol/l), or ChTx plus apamin (to block endothelium-derived hyperpolarizing factor; EDHF). Hyperemic responses to local injection of acetylcholine (2.4 µg/kg) were reproducible in vehicle-treated mice and were not significantly attenuated by L-NAME alone, indomethacin alone, L-NAME plus indomethacin with or without co-infusion of diethlyamine NONOate to restore resting NO levels, ChTx alone, or apamin alone. Hyperemic responses evoked by acetylcholine were reduced by 29 ± 11% after combined treatment with apamin plus charybdotoxin, and the remainder was virtually abolished by additional treatment with L-NAME but not indomethacin. None of the treatments altered the hyperemic response to sodium nitroprusside (5 µg/kg). We conclude that endothelium-dependent vasodilation in the mouse hindlimb in vivo is mediated by both NO and EDHF. EDHF can fully compensate for the loss of NO, but this cannot be explained by tonic inhibition of EDHF by NO. Control of basal vasodilator tone in the mouse hindlimb is dominated by NO.

endothelium-derived hyperpolarizing factor; nitric oxide; prostanoids

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