Antihypertensive and Renal Activity of SQ 28,603, an Inhibitor of Neutral Endopeptidase

Seymour, A A; Norman, Jon; Asaad, Magdi M.; Fennell, S A; Little, D K; Kratunis, V J; Rogers, W L

doi:10.1097/00005344-199102000-00016

Cited by 31 publications

(19 citation statements)

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“…As a result, they promote diuresis and natriuresis and lower blood pressure, espe cially in volume-dependent hypertension [54]. Of interest, these agents have also been shown to inhibit vascular smooth muscle cell proliferation in animal models of vascu lar injury [54].…”

Section: Beyond the Acei And Caamentioning

confidence: 99%

Protecting the Residual Renal Function: How Do ACE Inhibitors and Calcium Antagonists Compare?

Maschio¹

1994

Nephron

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Section: Beyond the Acei And Caamentioning

confidence: 99%

Protecting the Residual Renal Function: How Do ACE Inhibitors and Calcium Antagonists Compare?

Maschio¹

1994

Nephron

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“…Based on our results, it is unlikely that the surface peptidase(s) on CPA47 cells is NEP 24.11 or kallikrein, both of which are known to degrade ANP in vivo [4,5,20]. NEP 24.11 is a metalloprotease, the activity of which is inhibited by EDTA and phosphoramidon and not inhibited by carboxypeptidase inhibitor [201.…”

Section: Discussionmentioning

confidence: 97%

Characterization of atrial natriuretic peptide degradation by cell‐surface peptidase activity on endothelial cells

Frost

Whitson

1993

J of Cellular Biochemistry

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Atrial natriuretic peptide (ANP) is a fluid-regulating peptide hormone that promotes vasorelaxation, natriuresis, and diuresis. The mechanisms for the release of ANP and for its clearance from the circulation play important roles in modulating its biological effects. Recently, we have reported that the cell surface of an endothelial cell line, CPA47, could degrade 125I-ANP in the presence of EDTA. In this study, we have characterized this degradation of 125I-ANP. The kinetics of ANP degradation by the surface of CPA47 cells were first order, with a Km of 320 +/- 60 nM and Vmax of 35 +/- 14 pmol of ANP degraded/10 min/10(5) cells at pH 7.4. ANP is degraded by the surface of CPA47 cells over a broad pH range from 7.0-8.5. Potato carboxypeptidase inhibitor and bestatin inhibited 125I-ANP degradation, suggesting that this degradative activity on the surface of CPA47 cells has exopeptidase characteristics. The selectivity of CPA47 cell-surface degradation of ANP was demonstrated when 125I-ANP degradation was inhibited in the presence of neuropeptide Y and angiotensin I and II but not bradykinin, bombesin, endothelin-1, or substance P. The C-terminal amino acids phe26 and tyr28 were deduced to be important for ANP interaction with the cell-surface peptidase(s) based on comparison of the IC50 of various ANP analogues and other natriuretic peptides for the inhibition of ANP degradation. These data suggest that a newly characterized divalent cation-independent exopeptidase(s) that selectively recognizes ANP and some other vasoactive peptides exists on the surface of endothelial cells.

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“…Metalloendopeptidase inhibitors have been shown to potentiate the antihypertensive, haemodynamic and renal actions of ANP [12,13,18,[24][25][26][27]. To date only three studies have examined the effect of neutral endopeptidase inhibitors in chronic renal failure [4,28,29].…”

Section: Discussionmentioning

confidence: 99%

Effects of Neutral Endopeptidase Inhibition in the Rat Remnant Kidney Model

Jandeleit‐Dahm

Burrell

Kanazawa

et al. 1998

Kidney Blood Press Res

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The orally active neutral metalloendopeptidase (NEP) inhibitor SCH34826 was given by oral gavage in a dose of 90 mg/kg twice daily for 3 days to rats with subtotal nephrectomy (n = 7) and effects were compared to a placebo group receiving phosphate buffer (n = 5). Inhibition of neutral endopeptidase in the remnant kidney was measured by in vitro autoradiography using the specific radioligand [¹²⁵I]–SCH 47896. Treatment with the NEP inhibitor SCH34826 caused a 60% reduction in the neutral endopeptidase radioligand–binding site density in the kidneys of the SCH34826–treated animals compared to the placebo group (81.6±3.7 versus 214.5±4.2 dpm/mm², p<0.01). This was associated with a marked increase in urinary atrial natriuretic peptide (ANP) from 3,930±295 to 9,094±1,089 pg/24 h in the SCH34826–treated group (p<0.01). Concomitantly there was a transient increase in natriuresis in the SCH34826–treated group [baseline 2.03±0.55 to 3.77±0.58 mmol/24 h on treatment day 1 (p = 0.02) and 2.58±0.19 mmol/24 h on treatment day 3 (p = 0.09)] which was not observed in the placebo group. Urinary protein excretion, glomerular filtration rate (determined by ^99mTc–DTPA clearance), systemic blood pressure, plasma ANP concentration and urinary cyclic GMP excretion were not changed by SCH34826 treatment. These results suggest that oral administration of the NEP inhibitor SCH34826 inhibits renal neutral endopeptidase, increases urinary ANP and modulates natriuresis without alteration of systemic blood pressure, plasma ANP and renin level, glomerular filtration or protein excretion.

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Antihypertensive and Renal Activity of SQ 28,603, an Inhibitor of Neutral Endopeptidase

Cited by 31 publications

References 0 publications

Protecting the Residual Renal Function: How Do ACE Inhibitors and Calcium Antagonists Compare?

Protecting the Residual Renal Function: How Do ACE Inhibitors and Calcium Antagonists Compare?

Characterization of atrial natriuretic peptide degradation by cell‐surface peptidase activity on endothelial cells

Effects of Neutral Endopeptidase Inhibition in the Rat Remnant Kidney Model

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