Actions of Angeli's salt, a nitroxyl (HNO) donor, on ion transport across mucosa-submucosa preparations from rat distal colon.

The aim of this study was to investigate whether nitroxyl (HNO), a redox variant of the radical gasotransmitter nitric oxide (NO) with therapeutically promising properties, affects colonic ion transport. Changes in short-circuit current (Isc) induced by the HNO donor Angeli's salt were recorded in Ussing chambers. Cytosolic Ca(2+) concentration was measured with fura-2. The nitroxyl donor induced a concentration-dependent increase in Isc across rat distal colon which was due to a stimulation of chloride secretion. The secretion induced by Angeli's salt (5×10(-4)mol/l) was not altered by the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), but was abolished by the HNO scavenger l-cysteine. The response was not dependent on the activity of soluble guanylate cyclase or enteric neurons, but was inhibited by indomethacin. Experiments with apically permeabilized epithelia revealed the activation of basolateral K(+) channels and a stimulation of the current carried by the basolateral Na(+)-K(+)-pump by Angeli's salt. The secretion induced by Angeli's salt was reduced in the absence of extracellular Ca(2+). A prominent increase in the cytosolic Ca(2+) concentration was evoked by Angeli's salt predominantly in subepithelial cells within the submucosa, which had the same dependence on extracellular Ca(2+) as the Angeli's salt-induced Cl(-) secretion. Consequently, Angeli's salt induces a soluble guanylate cyclase-independent, Ca(2+)-dependent Cl(-) secretion via activation of the Na(+)-K(+)-ATPase and of basolateral K(+) channels. Cyclooxygenase metabolites produced within the submucosa seem to be involved in this response.