Nitroxyl (HNO) as novel player in the regulation of gastrointestinal motility

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An emerging class of regulators of gastrointestinal functions are gaseous molecules, the so-called gasotransmitters. There are two well-established gases with transmitter function in the gut: nitric oxide (NO) and hydrogen sulphide (H2S). Both induce gastrointestinal smooth muscle relaxation via different mechanisms. While NO activates soluble guanylate cyclase, the production of cGMP and consequently activates protein kinase G (or potentially directly activates K+ channels), H2S activates e.g. ATP-sensitive and small conductance Ca2+-dependent K+ channels.A third gasotransmitter, nitroxyl (HNO), whose actions on gastrointestinal motility shall be investigated in the present study, is getting more attention recently. All what is known about HNO regarding the gastrointestinal tract is that it exerts a prosecretory action, which is strongly dependent on Ca2+ and involves Ca2+-dependent and ATP-sensitive K+ channels and is in part mediated by cyclooxygenase metabolites (Pouokam et al. 2013). Preliminary experiments revealed that an HNO donor, Angelis salt, evokes intestinal relaxation measured at longitudinal strips from rat ileum and colon. The mechanisms underlying this relaxation shall be investigated in the present study by patch-clamp experiments at isolated myocytes, imaging experiments at spontaneously contracting smooth muscle cell reaggregates and isometric muscle contraction measurements. Special focus will be placed on the characterization of the involved ion conductances, the possible mediation by thiol group modification (due to the high thiophylic character of HNO) and the involvement of typical components of the cGMP signalling pathway. In parallel, preliminary experiments revealed a hyperpolarization of myenteric neurons concomitant with an inhibition of inward-currents carried by voltage-dependent Na+ channels. The ionic mechanisms underlying the change in membrane potential induced by HNO of myenteric neurons, i.e. the part of the enteric nervous system responsible for autonomous control of gut motility, are unknown and shall be identified in the present study.Recent studies in the literature showed a cross-talk between NO, H2S and HNO signalling pathways; for example exogenous H2S may interact with endogenous NO to form HNO, which rises the possibility that some actions of H2S may indeed be mediated by HNO. This hypothesis shall be investigated by testing the sensitivity of the relaxant response to H2S against identified inhibitors of the HNO-stimulated pathway. With these experiments it is hoped to get a better insight into the regulation of gastrointestinal motility by a new member of the emerging class of gasotransmitters.