Diuretic-natriuretic actions and pressor effects of big-endothelin (1-39) in phosphoramidon-treated rats

The effects of phosphoramidon, a metalloproteinase inhibitor, on the pressor and renal actions of big-endothelin (BET), the precursor of porcine Endothelin-1 (ET), was studied in rats. In control rats, BET (0.3, 1.0, and 3.0 nmol/kg) elicited a marked increase in mean arterial blood pressure (from 110 +/- 7 to 105 +/- 7, 120 +/- 8, 147 +/- 6 mm Hg, respectively), and a prominent, dose-dependent, diuretic and natriuretic response (fractional sodium excretion (FENa) increased from 0.4 +/- 0.2 to 0.8 +/- 0.2, 3.1 +/- 0.1, and 8.5 +/- 1.7%, respectively). Pretreatment with phosphoramidon (10 mg/kg + 0.25 mg/kg/min) completely abolished the increase in blood pressure induced by BET, but the diuretic-natriuretic effects were only partially inhibited (FENa increased from 2.0 +/- 0.9 to 3.7 +/- 1.5, 3.9 +/- 1.3, and 4.3 +/- 1.2%, respectively, P < 0.05). Rats treated with phosphoramidon only had no natriuresis over time (FENa changed from 1.9 +/- 0.5 to 2.3 +/- 0.3, 1.6 +/- 0.4, 1.7 +/- 0.6 respectively, P--NS). The data suggest that, unlike the vascular type of the enzyme, the renal endothelin converting enzyme is relatively insensitive to phosphoramidon. Further, diuresis and natriuresis can be induced by BET in the absence of any pressor effect.