Actions and interactions of endothelins, prostacyclin and nitric oxide in the gastric mucosa.
The modulation of the gastric mucosal microcirculation plays a key role in the maintenance of gastric integrity. Disruption of the balance between the local release of vasodilator and vasoconstrictor mediators could therefore be involved in the pathogenesis of mucosal injury. Thus, the endothelium derived peptide endothelin-1 (ET-1), induces mucosal injury following local administration. In contrast, the vasodilator prostanoids, prostacyclin and PGE2 can protect against gastric damage, while inhibition of endogenous prostanoid formation by cyclo-oxygenase inhibitors augment mucosal damage, including that induced by ET-1. Sensory neuropeptides such as calcitonin gene-related peptide (CGRP) may also play a local protective role, since acute intragastric administration of capsaicin which stimulates neuropeptide release, protects against mucosal injury induced by ET-1, as does local infusion of CGRP. Furthermore, chronic administration of capsaicin which deplete primary sensory neurones augments gastric damage induced by a number of ulcerogens including ET-1. Nitric oxide (NO) synthesized from L-arginine can regulate gastric mucosal blood flow, both under resting conditions and following stimulation of acid secretion. Inhibition of NO biosynthesis alone does not induce acute mucosal injury, yet extensive haemorrhagic damage results from concurrent inhibition of NO formation, cyclo-oxygenase inhibition and depletion of sensory neuropeptides. NO donors can protect against ulceration, although the unregulated release of high levels of NO can lead to mucosal injury. Thus, NO has a critical interactive role with other local protective mediators such as the prostanoids and sensory neuropeptides in the physiological regulation of mucosal integrity.
Whittle
B J
BJ
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent U.K.
Lopez-Belmonte
J
J
D000818:Animals; D016232:Endothelins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology*; D005753:Gastric Mucosa / Q000098:blood supply / Q000502:physiology*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*
D016232:Endothelins; D009569:Nitric Oxide; D011464:Epoprostenol