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The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat. Administration of either NG‐monomethyl‐l‐arginine (l‐NMMA) to inhibit endothelium‐derived NO formation, indomethacin to inhibit prostanoid biosynthesis or chronic capsaicin pretreatment to deplete sensory neuropeptides, did not induce acute mucosal injury. In capsaicin‐pretreated rats, however, l‐NMMA (12.5–100 mg kg−1 i.v.) dose‐dependently induced acute mucosal damage, characterized as vasocongestion and haemorrhagic necrosis. The enatiomer d‐NMMA (100 mg kg−1 i.v.) did not induce any detectable mucosal damage. This mucosal injury induced by l‐NMMA was inhibited by concurrent administration of l‐arginine (300 mg kg‐1 i.v.). In indomethacin (5 mg kg−1 i.v.)‐pretreated rats, l‐NMMA also induced mucosal damage. Furthermore, following indomethacin administration in capsaicin‐pretreated rats, l‐NMMA induced widespread, severe haemorrhagic necrotic damage. These findings suggest a role for endogenous NO formed from l‐arginine, acting in concert with prostacyclin and sensory neuropeptides, in the modulation of gastric mucosal integrity.

1 The effect of endotoxin (E. coli lipopolysaccharide) on the induction of nitric oxide synthase (NOS) and the changes in vascular permeability in the colon and jejunum over a 5 h period have been investigated in the rat. 2 Under resting conditions, a calcium-dependent constitutive NOS, determined by the conversion of radiolabelled L-arginine to citrulline, was detected in homogenates of both colonic and jejunal tissue. 3 Administration of endotoxin (3 mg kg-', i.v.) led, after a 2 h lag period, to the appearance of calcium-independent NOS activity in the colon and jejunum ex vivo, characteristic of the inducible NOS enzyme. 4 Administration of endotoxin led to an increase in colonic and jejunal vascular permeability after a lag period of 3 h, determined by the leakage of radiolabelled albumin. 5 Pretreatment with dexamethasone (1 mg kg-' s.c., 2 h prior to challenge) inhibited both the induction of NOS and the vascular leakage induced by endotoxin. 6 Administration of the NO synthase inhibitor NG-monomethyl-L-arginine (12.5-50mg kg-', s.c.) 3 h after endotoxin injection, dose-dependently reduced the subsequent increase in vascular permeability in jejunum and colon, an effect reversed by L-arginine (300 mg kg-', s.c.). 7 These findings suggest that induction of NOS is associated with the vascular injury induced by endotoxin in the rat colon and jejunum.

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The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.