Electroneutral ion transport processes such as Na-K-Cl cotransport are important in vectorial salt and water movement across many epithelial tissues involved in fluid and electrolyte regulation in vertebrate animals. Na-K-Cl cotransport is known to play an important role in tubular reabsorption in the thick ascending limb of Henle's loop in the kidney. In many cases, diseases related to hypertension are controlled, in part, by inhibition of this transport system with """"""""loop"""""""" diuretics such as furosemide or bumetanide. Recently it was established that mammalian atrial cardiocytes produce a natriuretic and diuretic substance called atrial natriuretic factor (ANF) which causes a prompt and massive natriuresis and diuresis of short duration. Its effects on GFR and its hemodynamic actions have been described in a number of laboratories, but its effects on electrolyte transport have been controversial and, until very recently, poorly documented. Recent studies with ANF on ion transport in the isolated intestinal epithelium of the winter flounder have shown that ANF is a potent inhibitor of epithelial ion transport in this tissue. The intestine of the flounder possesses a well characterized Na-K-Cl cotransport system which is inhibitable with loop diuretics and by increases in intracellular cGMP. It is a simple, relatively homogeneous epithelium similar in its transport properties to the thick ascending limb of Henle's loop in mammalian kidney. The major goals of this proposal are to establish the mechanism of inhibition of ion transport by ANF and to determine whether an ANF-like peptide serves as an endogenous regulator of intestinal ion transport in the winter flounder. This will require: 1) identification of the specific second messengers which mediate the intracellular events responsible for inhibition of ion transport, 2) characterization of ANF receptors in the intestine and their relationship to the production of second messengers and 3) identification and characterization of ANF-like peptides produced by the flounder followed by a comparison of their physical properties and natriuretic and diuretic activities with mammalian forms of ANF. Results from these studies should be useful in understanding some of the cellular mechanisms underlying effects of these peptides in diverse tissues and also provide some insight into how ion transport is regulated and modified by diuretics in mammalian kidney and, more specifically, in the thick ascending limb of Henle's loop.
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