Table 4.

Criteria for vasodilator substances

	Criteria for Vasodilator Substances
1	The substance or substances (or their precursors) thought to cause vasodilation should be present in the tissue or tissues thought to release them. These tissues could include skeletal muscle, vascular smooth muscle, the vascular endothelium, blood, or nerves.
2	The substance or substances should have access to the muscle resistance vessels.
3	The concentration of the substance in the interstitial fluid or at the vascular endothelium should be sufficient to cause dilation in a concentration-dependent manner that is related to contractile activity.
4	Exogenous administration of the substance or substances should be capable of causing prolonged dilation without sensations in humans.
5	Pharmacological agents or physiological maneuvers that alter the blood flow responses to exercise should have similar effects on the vasodilator responses to any putative substances given exogenously.

These concepts were adapted from Shepherd (431). The major additions in these criteria since the original criteria of Shepherd include the discovery of the vascular endothelium as a key site of vascular control.