Enhanced release of endothelium-derived factor(s) by chronic increases in blood flow.

Chronic increases in blood flow caused by an arteriovenous fistula augment endothelium-dependent relaxations to acetylcholine. To determine whether endothelial muscarinic receptors are altered, concentration-response curves to acetylcholine were obtained in the presence of pirenzepine in fistula- and sham-operated canine femoral arteries. Pirenzepine inhibited the response to acetylcholine in both arteries. The pA2 (log Kb) for the antagonist was the same. A bioassay system was used to assess release of endothelium-derived relaxing factor. Rings of femoral artery (without endothelium) from unoperated dogs relaxed more when superfused with perfusate derived from endothelium of fistula-operated arteries during acetylcholine stimulation. Rings without endothelium of sham- and fistula-operated arteries relaxed to the same extent when superfused with perfusate derived from the endothelium of unoperated femoral arteries. These results suggest that augmented relaxations to acetylcholine in canine arteries where blood flow is chronically elevated do not result from changes in the subtype of endothelial muscarinic receptors or in the sensitivity of the underlying smooth muscle to endothelium-derived relaxing factor(s). They are likely due to increased release of endothelium-derived relaxing factor(s) on muscarinic activation.