Renal effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine, a novel selective inhibitor of neutral endopeptidase 24.11 (Neprilysin): comparison with SQ 28,603.

The effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine (MA-LF) on the activity of neutral endopeptidase and on renal hemodynamics and excretory function were investigated in experiments in vitro and in vivo. In vitro studies showed that the compound effectively inhibited purified bovine kidney neutral endopeptidase (Ki = 0.012 microM), while having slight influence on the activity of angiotensin I converting enzyme (Ki = 0.14 microM). In experiments on normal anesthetized rats (thiobutabarbital sodium salt, 100 mg/kg), IV administration of MA-LF (20 and 60 mg/kg) produced a dose-dependent increase in absolute rate and fractional excretion of sodium (+324% and +299%, respectively) and urinary flow rate (+261%), but did not change renal and systemic hemodynamics. Renal excretory effects of the new compound were comparable to those of the selective neutral endopeptidase inhibitor SQ 28,603. These results demonstrate that MA-LF is a potent neutral endopeptidase inhibitor with prominent natriuretic and diuretic properties.

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.

Effect of atrial natriuretic factor on renal cGMP production in rats with adriamycin-induced nephrotic syndrome.

Adriamycin-induced nephrotic syndrome in the rat is associated with a blunted natriuretic response to infusion of atrial natriuretic factor. To study the mechanism of renal hyporesponsiveness to the peptide in rats with experimental nephrosis, we evaluated the effects of the hormone on renal production of cGMP, the second messenger of the hormone. Baseline GFR and sodium excretion were lower in nephrotic as compared with normal controls. Infusion of synthetic rat atrial natriuretic factor (10 micrograms/kg/h) increased fractional sodium excretion by 7.3 +/- 2.4% in control rats but only by 1.4 +/- 0.5% in adriamycin-treated rats (P less than 0.05). However, the increments in urinary nucleotide excretion rate (UcGMP x V/GFR), in response to atrial natriuretic factor infusion, were comparable in control and nephrotic rats (control, 114.7 +/- 16.1 pmol/mL; adriamycin, 95.5 +/- 12.0 pmol/mL; P was not significant). The in vitro generation of cGMP in response to incremental doses of the hormone (10(-11) to 10(-6) M + 1 mM 3-isobutyl methyl xanthine) was of similar magnitude in isolated glomeruli derived from control (2.4 +/- 0.25 to 9.1 +/- 1.0 pmol/mg of protein) and nephrotic rats (2.9 +/- 0.2 to 10.3 +/- 1.0 pmol/mg of protein) and was not impaired in suspensions of medullary tissue derived from nephrotic rats (control, 8.4 +/- 0.6 to 14.2 +/- 1.2 pmol/mg of protein; adriamycin, 7.3 +/- 0.7 to 22.0 +/- 2.4 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)