Endothelium-derived relaxing factors. A perspective from in vivo data.

Abstract

We review below published studies of endothelium-dependent vasodilation in vivo. Endothelium-dependent vasodilation has been demonstrated in conduit arteries in vivo and in the cerebral, coronary, mesenteric, and femoral vascular beds as well as in the microcirculation of the brain and the microcirculation of cremaster muscle. The available evidence, although not complete, strongly suggests that the endothellum-derived relaxing factor generated by acetylcholine in the cerebral microcirculation is a nitrosothiol. The endothelium-derived relaxing factor generated by bradykinin in this vascular bed is an oxygen radical generated in association with enhanced arachidonate metabolism via cyclooxygenase. In the microcirculation of skeletal muscle, on the other hand, the vasodilation from bradykinin is mediated partly by prostacycline and partly by an endothelium-derived relaxing factor similar to that generated by acetylcholine. Basal secretion of endothelium-derived relaxing factor is controversial in vivo but is usually present in vitro. On the other hand, it appears that endothelium-derived relaxing factor mediates flow-dependent vasodilation in both large vessels and in the microcirculation in vivo. The generation and release of endothelium-derived relaxing factor from endothelium may be abnormal in a variety of conditions including acute and chronic hypertension, atherosclerosis, and ischemia followed by reperfusion. Several mechanisms for these abnormalities have been identified. These include inability to generate endothelium-derived relaxing factor or destruction of endothelium-derived relaxing factor by oxidants after its release in the extracellular space. These abnormalities in endothelium-dependent relaxation may contribute to the vascular abnormalities in these conditions. (Hypertension 1990;16:371-386) T he discovery of endothelium-derived relaxing factor (EDRF) generated by acetylcholine 1 opened a new field of investigation into endothelium-derived vasoactive factors. It is now well established that a number of vasoactive agents indirectly induce vascular smooth muscle relaxation with ensuing vasodilation by acting on the endothelium to induce the generation and release of EDRFs. These substances are short-lived (Figure 1). Therefore, the final pathway for the vasodilation induced by EDRF is the same as that for the nitrodilators, which generate nitric oxide either spontaneously

Oxidants, antioxidants and the ischemic brain

“…Since the original suggestion that nitric oxide synthesis plays a role in cerebral ischemia (Marshall and Kontos, 1990), over 800 research reports have addressed this issue. Nitric oxide is enzymatically synthesized from L-arginine and is massively increased by ischemia (Wei et al, 1999).…”

Mechanisms of H2O2-induced oxidative stress in endothelial cells

“…Cyclooxygenase produces O 2 ·-through its ability to oxidize NADPH and alternative substances to NADP·, which autoxidizes O 2 resulting in O 2 ·- (Kukreja et al 1986). Cyclooxygenase is also capable of generating significant quantities of ROS while producing prostaglandins such as PGH 2 (Holland et al 1990;Marshall et al 1990). …”

Functional Increases in Cerebral Blood Volume over Somatosensory Cortex

“…While trends remain intact, such effects prevent the numerical interpretation of fluorescence intensity as plasma (dye) volume when comparing pre-and poststimu Ius states. Furthermore, cortical trauma during preparation might introduce additional errors since mechanical trauma, photochemical procedures, and fluorescent compounds all abnormally influence en dothelial vasoreactivity (Rosenblum, 1986;Haberl et ai., 1990;Marshall and Kontos, 1990).…”