• Cholinergic and adrenergic nerve endings in a blood vessel wall
• The endothelium is required for vascular relaxation in response to acetylcholine

Vasorelaxation mediated by nitric oxide is controlled by the autonomic nervous system. The physiological experiments that uncovered the role of the endothelium, and subsequently of NO, in vasorelaxation are simple yet ingenious. In order to appreciate them, we need a little more anatomy.

We had seen earlier that both the sympathetic and the parasympathetic nervous system innervate blood vessel walls and regulate their contraction and wall tension (slide 6.13.1). The adrenergic nerve endings of the sympathetic nerve fibers are found in the muscular layer of the vessel walls. In contrast, cholinergic nerve endings are found both in the muscular and the endothelial layers.

The wall tension of the blood vessel is sustained by the muscular layer, not the endothelium; therefore, the cholinergic innervation of the endothelium is surprising. As it turns out, however, it is needed for the vasorelaxation and vasodilation induced by the parasympathetic system.

This slide illustrates the experiment that led to the discovery of nitric oxide-mediated vasorelaxation.

Contraction and relaxation of the vascular smooth muscle cells in response to norepinephrine and acetylcholine were studied with aortic strips. In this technique, slices are cut from an animal’s aorta and then opened with a radial incision. The endothelium can be left in place or peeled away in order to study its effect on the muscular layer. The resulting intact or denuded aortic strips were mounted between two distending hooks to measure their contractile force.

Application of norepinephrine induced contraction in strips with or without attached endothelium, as would be expected from the innervation pattern of the sympathetic nerve fibers. In contrast, norepinephrine-induced contraction could be reversed by acetylcholine only if the strip retained the endothelium (top) but not when the endothelium had been peeled away.

Interestingly, relaxation of a denuded muscular strip could be restored if the endothelial side of an intact strip was strapped onto it (not illustrated). This observation showed that, in response to cholinergic stimulation, the endothelium releases a diffusible substance that enters the muscular layer and induces its relaxation. This “endothelium-derived relaxing factor” was subsequently isolated and identified as NO.