Since endothelin has been localized in neurons in areas involved in water and electrolyte metabolism, areas which also contain atrial natriuretic peptide (ANP) neurons, we determined whether endothelin would release ANP and induce natriuresis. Endothelin-3 (ET-3) in doses ranging from 38 to 760 pmol was microinjected into the third ventricle (3V) of conscious, water-loaded male rats, and the effect on natriuresis and plasma ANP was determined. ET-3 evoked a dose-related natriuresis beginning within 20 min of injection. Even the lowest dose tested (38 pmol) was effective. At a dose of 95 pmol, it produced a rapid increase of plasma ANP within 5 min peaking at 20 min. A slight kaliuresis and antidiuresis was observed at the 2 highest doses of 380 and 760 pmol. The urinary changes following 3V injection of ET-3 were similar to those evoked by ANP, except for the antidiuresis with increased sodium concentration which followed injection of the 2 higher doses. These results suggest that these 2 higher doses also released vasopressin. Alternatively, activation of the sympathetic nervous system by these higher doses may have decreased glomerular filtration rate and been in part responsible for the antidiuresis. The results with 3V injection of ET-3 contrasted sharply with those obtained following intravenous injection of the 95-pmol dose injected intra-ventricularly. This intravenous dose of ANP induced a transient decrease in sodium and potassium excretion and urine volume, maximal at 20 min, and had no effect on plasma ANP concentrations at 5 or 20 min after injection. Previous experiments have shown that the hypothalamic ANP neuronal system plays an essential role in the volume expansion-induced release of ANP and the subsequent natriuresis. We speculate that endothelin released in the brain following volume expansion may activate the ANP neuronal system which is then followed by an increased release of ANP from the atria and possibly from the brain. Further experiments will be necessary to validate this hypothesis.

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