Atrial Natriuretic Factor Potentiating and Hemodynamic Effects of SCH 42495, a New, Neutral Metalloendopeptidase Inhibitor

Watkins, Robert W.; Vemulapalli, Subbarao; Chiu, Peter; Foster, Carolyn; Smith, Elizabeth M.; Neustadt, Bernard R.; Haslanger, Martin F.; Sybertz, Edmund J.

doi:10.1093/ajh/6.5.357

Cited by 9 publications

(17 citation statements)

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“…The concentration of SCH 42354 that displaced 50% of specific NEP binding (ICSO) was 3.3 & 0.1 nmol/l (mean f SEM; n = 3). The ICSO obtained using 12sI-labelled RB104 is in agreement with published results using an enzymic assay and rabbit renal membranes (1% = 8.3 f 4 nmol/l) [9]. In contrast, enalaprilat had no effect on selective NEP radioligand binding in rat renal membranes.…”

Section: Ri Basupporting

confidence: 90%

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Inhibition of Neutral Endopeptidase, the Degradative Enzyme for Natriuretic Peptides, in rat Kidney after Oral SCH 42495

et al. 1997

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1. Inhibition of neutral endopeptidase (NEP), the degradative enzyme for atrial natriuretic peptide, was studied in vitro and in vivo using a previously characterized NEP inhibitor radioligand, 125I-labelled RB104. 2. SCH 42354, the active di-acid of the ethylester prodrug, SCH 42495, caused a concentration-dependent displacement of 125I-labelled RB104 from rat renal NEP. The concentration of SCH 42354 that displaced 50% of radioligand bound to the enzyme NEP (IC50) was 3.3 +/- 0.1 nmol/l (mean +/- SEM). Enalaprilat, an angiotensin converting enzyme inhibitor, did not displace 125I-labelled RB104 in concentrations up to 10 mumol/l. 3. In adult normotensive Sprague-Dawley rats, oral SCH 42495 (3-300 mg/kg) caused significant inhibition of renal NEP (P < 0.001). SCH 42495 had no effect on renal or plasma angiotensin converting enzyme activity, but high-dose SCH 42495 (300 mg/kg) caused a significant increase in plasma renin activity (P < 0.01). 4. In a time course study, oral SCH 42495 (30 mg/kg) caused rapid (within 30 min) and significant inhibition of renal NEP for up to 48 h (P < 0.001). No changes in plasma atrial natriuretic peptide or plasma angiotensin converting enzyme activity were seen. 5. These data provide evidence that short-term administration of the NEP inhibitor SCH 42495 results in inhibition of renal NEP and does not inhibit the circulating or the tissue renin-angiotensin system. The NEP inhibitor radioligand 125I-labelled RB104, is a useful tool to study tissue NEP inhibition after administration of NEP inhibitors.

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Section: Ri Basupporting

confidence: 90%

“…Oral SCH 42495 (30 mglkg) caused no change in plasma ANP concentration or plasma ACE activity. HL, histidyl leucine.inhibitors on plasma ANP levels, despite their producing biological responses; other studies show a clear rise in plasma ANP with NEP inhibition in rats[9], sheep [32, 331 and man…”

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Inhibition of Neutral Endopeptidase, the Degradative Enzyme for Natriuretic Peptides, in rat Kidney after Oral SCH 42495

et al. 1997

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“…Similar results have also been reported with the less potent (Watkins et al, 1993) compound, SCH 34826 (Stewart et al, 1992, and the structurally unrelated drug, Candoxatrilat . However, in this latter study, Winter et al observed a significant elevation of plasma ANP levels in rats treated with Candoxatrilat during seven days exposure to hypoxia and proposed that the mechanism by which NEP inhibition reduced pulmonary vascular remodelling was by elevation of plasma ANP levels.…”

Section: Discussionsupporting

confidence: 79%

“…Watkins et al (1993) demonstrated that the in vivo hypotensive response to SCH 42495 (3 and 30 mg kg-'), seen in volume expanded rats, was not affected by intravenous administration of two substrates of ACE, bradykinin or angiotensin II. Similarly, Sybertz et al.…”

Section: Discussionmentioning

confidence: 95%

“…Because of this dual pathway of clearance, attempts to elevate plasma ANP solely by inhibiting NEP have met with limited success. However, NEP inhibition does prolong the half life of ANP, elevate plasma ANP levels, and cause diuresis on volume loading in rats (Watkins et al, 1993), normal human volunteers (Danielwicz et al, 1989) and patients in chronic heart failure (Northridge et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

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Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia

Thompson

Sheedy

Morice

1994

British J Pharmacology

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1Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2 One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3 Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NClO) and all other animals were placed in a normobaric hypoxic chamber (Fi 02 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-', twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4 Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5 CHClO rats had significant right ventricular hypertrophy (0.53 ± 0.08) and pulmonary vascular remodelling (29.0 0.01%) and had gained significantly less body weight (33.2 ± 5.5 g) than NC1O rats (0.31 ± 0.04, 10.9 0.01%, and 59.2 ± 11.9 g respectively). CHC1O rats had significantly elevated plasma ANP levels (58.4 ± 9.9 pM) compared with NClO rats (23.9 ± 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 ± 0.01%) and right ventricular hypertrophy (0.52 ± 0.09) in CHT20 rats compared with CHV20 controls (33.0 ± 0.02% and 0.61 ± 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals. 6 Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.

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Sinorphan Improves Cardiac Structure and Function in Aged Stroke-Prone Spontaneously Hypertensive Rats

Knorr

Hirth-Dietrich

Stasch

1995

Experimental Hypertension and Therapeutic Progress: Vasodilation and Beyond

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Atrial Natriuretic Factor Potentiating and Hemodynamic Effects of SCH 42495, a New, Neutral Metalloendopeptidase Inhibitor

Cited by 9 publications

References 0 publications

Inhibition of Neutral Endopeptidase, the Degradative Enzyme for Natriuretic Peptides, in rat Kidney after Oral SCH 42495

Inhibition of Neutral Endopeptidase, the Degradative Enzyme for Natriuretic Peptides, in rat Kidney after Oral SCH 42495

Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia

Sinorphan Improves Cardiac Structure and Function in Aged Stroke-Prone Spontaneously Hypertensive Rats

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