To analyze the potential mediator(s) involved in flow-induced endothelium-dependent vasodilation, we measured the wall tension of intraluminally perfused canine femoral artery segments and compared the content of 6-ketoprostaglandin F1 alpha (determined by radioimmunoassay) and the relaxing activity of the effluent (determined by bioassay on canine coronary artery rings). During perfusion at a steady flow of 2 ml/min the effluent contained 6-keto-prostaglandin F1 alpha and relaxed the bioassay rings. Sudden increase in steady flow rate to 4 ml/min, or the introduction of pulsatile flow, increased the release of 6-keto-prostaglandin F1 alpha and induced further relaxations of the bioassay ring. No relaxations were observed with the effluent passing through a femoral artery segment without endothelium. Indomethacin significantly depressed the release of 6-keto-prostaglandin F1 alpha during increases in flow but had no significant effect on the relaxing activity of the effluent. In the presence of indomethacin, increases in flow produced significant relaxation in the perfused femoral artery segments with endothelium. Superoxide dismutase restored the relaxing activity of the effluent during increases in flow at a transit time of 30 seconds. These data demonstrate that in addition to prostacyclin, flow triggers the release of another relaxing substance (or substances) from vascular endothelial cells that has characteristics similar to the endothelium-derived relaxing factor released by acetylcholine.

Experiments were designed to determine the contribution of endothelial cells to the heterogeneous behavior of the arterial and venous wall. Rings of canine femoral, pulmonary, saphenous, and splenic arteries and veins, with and without endothelium, were mounted for isometric tension recording in Krebs-Ringer bicarbonate solution. Endothelium-dependent inhibitory responses to acetylcholine, adenosine triphosphate, bovine thrombin, and arachidonic acid were prominent in the arteries. In the veins, only transient endothelium-dependent relaxations to these substances were observed. Removal of the endothelium decreased the augmentation of the response to norepinephrine caused by anoxia in both arteries and veins. In the veins, arachidonic acid and thrombin caused endothelium-dependent increases in tension during contractions evoked by norepinephrine. The endothelium-independent inhibitory effects of isoproterenol and adenosine and the excitatory effects of acetylcholine and ATP were more pronounced in the veins than in the arteries. These experiments demonstrate that in the arterial and venous wall the endothelial cells can contribute to both inhibitory and excitatory responses of the smooth muscle cells of the media. Inhibitory endothelial responses prevail in the arteries, and excitatory ones in the veins.

Endothelium-dependent relaxations that are resistant to inhibitors of nitric oxide synthase probably are mediated by endothelium-dependent hyperpolarization of the vascular smooth muscle. Experiments were performed to examine the distribution of this type of relaxation along the arterial tree of the rat by measuring changes in isometric force. Acetylcholine induced concentration- and endothelium-dependent relaxations in aortas and in pulmonary, common iliac, femoral, mesenteric, and renal arteries contracted with phenylephrine. In the presence of NG-nitro-L-arginine, the cumulative administration of acetylcholine induced relaxations only in the femoral, mesenteric, and renal arteries. The calcium ionophore A23187 relaxed mesenteric arteries contracted with phenylephrine in a concentration- and endothelium-dependent manner. The concentration-relaxation curve to A23187 was shifted to the right in the presence of NG-nitro-L-arginine. The maximal relaxations induced by lemakalim, a K+ channel opener, were smaller in those arteries that did not exhibit NG-nitro-L-arginine-resistant relaxations. These results suggest that NG-nitro-L-arginine-resistant relaxations are more frequently observed in smaller arteries. The arteries that exhibit NG-nitro-L-arginine-resistant relaxations may be more sensitive to an endothelium-derived substance that causes hyperpolarization of vascular smooth muscle cells.

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Stretch applied to isolated canine basilar arteries caused the development of active tension in rings with endothelium but not in those in which the endothelium had been removed. Blockade of calcium entry with diltiazem or inhibition of cyclooxygenase with indomethacin abolished the endothelium-dependent response to stretch. These observations suggest that the endothelium may contribute to the autoregulation of cerebral blood flow during increases in transmural pressure by the increased production and/or release of prostaglandins, which causes activation of the underlying vascular smooth muscle.