The lysine-1 analog of guanylin induces intestinal secretion and natriuresis in the isolated perfused kidney

ABSTRACT

Guanylin is an endogenous peptide synthesized by several mammalian species that mimics the effects of a thermostable enterotoxin of Escherichia coli (STa NTFYCCELCCNPACAGCY) in the gut. We have cloned a lysine-1 derivative of rat guanylin (Lys-1-NTCEICAYAACTGC) and tested its effects 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 enterotoxin peptide on chloride secretion were determined by changes in short-circuit current (Isc). Lys-1 G (10 to 100 nM) showed a dose-dependent effect on chloride secretion with a maximal response estimated to be 52 microA/cm2. Lys-1 G mimics the effect of STa peptide, but the enterotoxin elicited a greater maximal effect of 120 microA/cm2 (p<0.01). Lys-1 G (2.5 microg/ml) promoted an increase in both urine flow (from 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 ml g(-1) min(-1), N = 4; P<0.01) in the isolated perfused kidney and a reduction of the fractional reabsorption of sodium (from 76.0 +/- 0.03 to 59.5 +/- 0.85 percent, N = 4; P<0.01). These maximal effects were accompanied by intense natriuretic effect observed 30 and 60 min after drug administration. The Lys-1 G analog similar to STa enterotoxin elicited intestinal chloride secretion and a natriuretic effect. These data demonstrate that the cloned peptide analog retains the biological activity of the native hormone and presents activity similar to STa. The properties of Lys-1 G resemble those of a factor formed during perfusion of the hypoxic rabbit kidney and named by us factor natriureticus similis (FNS).