5-Hydroxytryptamine 4 (5-HT 4 ) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT 4 receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT 4 receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K + channel and tegaserod: 5-HT 1 and 5-HT 2 receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT 4 receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT 4 receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT 4 receptor-related differences between agonists. Based on drug-and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT 4 receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT 4 receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders.

Pre-treatment with CO-RMs markedly reduced IM-induced intestinal muscularis inflammation. These protective effects are, at least in part, mediated through induction of HO-1, in a p38-dependent manner, as well as reduction of ERK1/2 activation. In addition, CORM-induced HO-1 induction reduces the early "oxidative burst" in the mucosa following IM.

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PFL is more useful and sensitive than BPL for prognostic purposes in horses with colic.

1 The contribution of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) to non-adrenergic non-cholinergic (NANC) relaxations in the pig gastric fundus was investigated. 2 Circular and longitudinal muscle strips were mounted for isotonic registration in the presence of atropine and guanethidine; tone was raised with 5-hydroxytryptamine. Electrical field stimulation with 10 s trains at 5 min intervals induced short-lasting, frequency-dependent relaxations while continuous stimulation with cumulative increase of the stimulation frequency induced sustained frequency-dependent relaxations in both types of strips; the electrically induced responses were abolished by tetrodotoxin. 3 The short-lasting as well as the sustained electrically induced NANC relaxations were significantly reduced by N-nitro-L-arginine methyl ester (L-NAME). Pretreatment with L-arginine but not Darginine, prevented the inhibitory effect of L-NAME except for sustained relaxations in the longitudinal muscle strips. 4 Sodium nitroprusside, forskolin, zaprinast and 3-isobutyl-1-methylxanthine induced concentrationdependent relaxations. Exogenous NO mimicked the short-lasting electrically induced relaxations, while endogenous VIP evoked sustained relaxations. The responses to exogenous NO and VIP were not influenced by tetrodotoxin and L-NAME. 5 a-Chymotrypsin abolished the responses to exogenous VIP but only moderately reduced NANC relaxations induced by continuous electrical stimulation. Zaprinast potentiated the relaxant responses to sodium nitroprusside and increased the duration of the NANC relaxations induced by electrical stimulation with 10 s trains in circular muscle strips but not in longitudinal muscle strips. 6 The cyclic GMP and cyclic AMP response to electrical stimulation, NO and VIP was measured in circular muscle strips. Short-lasting as well as sustained electrical field stimulation induced an approximately 1.5 fold increase in cyclic GMP content, while NO induced nearly a 40 fold increase. An increase in cyclic AMP content was obtained only with sustained electrical field stimulation. 7 Immunocytochemistry for NO synthase (NOS) revealed immunoreactive neuronal cell bodies in the submucous and myenteric plexuses and nerve fibres in both the circular and longitudinal muscle layer; double-labelling for NOS and VIP showed that VIP coexists in a major part of the intrinsic neurones. NADPH diaphorase-histochemistry showed the same pattern of nitrergic neurones and nerves as NOSimmunocytochemistry. 8 It is concluded that a cyclic GMP-and a cyclic AMP-dependent pathway for relaxation is present in both the circular and longitudinal muscle layer of the pig gastric fundus. NO appears to contribute to short-lasting as well as sustained NANC relaxations. A peptide, possibly VIP, may be involved during sustained stimulation at lower frequencies of stimulation.