THE LYSINE-1 ANALOG OF GUANYLIN INDUCES INTESTINAL SECRETION AND NATRIURESIS IN THE ISOLATED-PERFUSED KIDNEY

Guanylin is an endogenous peptide synthesized by several mammalian spe cies that mimics the effects of a thermostable enterotoxin of Escheric hia coli (STa: NTFYCCELCCNPACAGCY) in the gut, We have cloned a lysine -1 derivative of rat guanylin (Lys-1-NTCEICAYAACTGC) and tested its ef fects on ileal tissue membranes in Ussing chambers and in the isolated perfused rat kidney. Rabbit ileal mucosa membranes were mounted into a Ussing chamber and the effects of Lys-1 guanylin (Lys-1 G) and STa e nterotoxin peptide on chloride secretion were determined by changes in short-circuit current (Isc), Lys-l G (10 to 100 nM) showed a dose-dep endent effect on chloride secretion with a maximal response estimated to be 52 mu A/cm(2). Lys-l G mimics the effect of STa peptide, but the enterotoxin elicited a greater maximal effect of 120 mu A/cm(2) (P<0. 01), Lys-l G (2.5 mu g/ml) promoted an increase in both urine flow (fr om 0.13 +/- 0.07 to 0.40 +/- 0.01 ml g(-1) min(-1),N = 4; P<0.05) and glomerular filtration rate (from 0.68 +/- 0.02 to 0.85 +/- 0.00 mi g(- 1) min(-1), N = 4; P<0.01) in the isolated perfused kidney and a reduc tion of the fractional reabsorption of sodium (from 76.0 +/- 0.03 to 5 9.5 +/- 0.85%, N = 4; P<0.01). These maximal effects were accompanied by intense natriuretic effect observed 30 and 60 min after drug admini stration, The Lys-l G analog similar to STa enterotoxin elicited intes tinal. chloride secretion and a natriuretic effect. These data demonst rate that the cloned peptide analog retains the biological activity of the native hormone and presents activity similar to STa. The properti es of Lys-l G resemble those of a factor formed during perfusion of th e hypoxic rabbit kidney and named by us factor natriureticus similis ( FNS).