Dual Inhibition of Angiotensin-Converting Enzyme and Neutral Endopeptidase in Rats with Hypertension

French, John F.; Anderson, Barbara A.; Downs, Thomas R.; Dage, Richard C.

doi:10.1097/00005344-199507000-00017

Cited by 61 publications

(43 citation statements)

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“…This agent, designed as the [7.5 in the absence (control, prodrug RB1O1, produced a potent analgesic response in M phosphodiepryl 08 (right murine species through the elevation of extracellular levels of cidification and analysed by enkephalins (Noble et al, 1992). French et al (1994) also (French et a!., 1994).…”

Section: Effect Of Phosphodiepryl 08 On Peripheral Neurotensin Degradmentioning

confidence: 94%

Phosphorus‐containing peptides as mixed inhibitors of endopeptidase 3.4.24.15 and 3.4.24.16: effect on neurotensin degradation in vitro and in vivo

Vincent¹,

Dive²,

Yiotakis³

et al. 1995

British J Pharmacology

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1 We have examined several phosphorus-containing peptides as potential mixed inhibitors of two neurotensin-degrading zinc metallopeptidases, endopeptidase 3.4.24.15 and endopeptidase 3.4.24.16. 2 Among a series of 13 phosphonamide peptides, N-(2-(2-naphtyl)ethylphosphonyl-glycyl-prolylnorleucine (phosphodiepryl 08) was found to inhibit potently the hydrolysis of neurotensin by purified 3 Phosphodiepryl 08 displayed a strong selectivity towards the two peptidases since it failed to inhibit several other zinc-containing peptidases such as endopeptidase 3.4.24.11, angiotensin-converting enzyme, aminopeptidase M, leucine aminopeptidase and carboxypeptidases A and B. 4 The protective effect of phosphodiepryl 08 on neurotensin degradation was examined in vitro and in vivo in central and peripheral bioassays. 5 Phosphodiepryl 08 virtually abolished neurotensin degradation by 4-day-old plated pure cultured neurones from mouse embryos and greatly potentiated neurotensin-induced antinociception in the mouse hot plate test. 6 In the periphery, phosphodiepryl 08 inhibited neurotensin degradation by membranes prepared from isolated longitudinal smooth muscle of guinea-pig ileum and greatly potentiated the neurotensin-induced contraction of the same longitudinal smooth muscle preparation. 7 Our study indicates that phosphodiepryl 08 behaves as a potent and selective mixed inhibitor of endopeptidase 3.4.24.15 and 3.4.24.16 and can be used as a powerful agent to prevent neurotensin degradation, in vitro and in vivo, in central and peripheral assays.

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Section: Effect Of Phosphodiepryl 08 On Peripheral Neurotensin Degradmentioning

confidence: 94%

Phosphorus‐containing peptides as mixed inhibitors of endopeptidase 3.4.24.15 and 3.4.24.16: effect on neurotensin degradation in vitro and in vivo

Vincent¹,

Dive²,

Yiotakis³

et al. 1995

British J Pharmacology

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“…These observations are consistent with those in other species. In conscious rats (both normotensive and hypertensive) (Pham et al, 1993;French et al, 1995;Vera et al, 1995) and in conscious dogs with pacinginduced heart failure (Seymour et al, 1993), dual inhibition of both enzyme systems is followed by falls in mean arterial pressure. In contrast, in healthy normotensive men, mean arterial pressure appears to be unaffected (Motwani et al, 1995).…”

Section: Effects Of Hoe 140 In Conscious Rabbitsmentioning

confidence: 99%

“…Combined inhibition of ACE and EP 24.11 also consistently increases urinary excretion of cyclic guanosine monophosphate, atrial natriuretic peptide and bradykinin (Pham et al, 1993;Seymour et al, 1993;French et al, 1995;Vera et al, 1995). These observations suggest that inhibition of both atrial natriuretic peptide and bradykinin metabolism within the kidney as well as suppression of the renin angiotensin system, might contribute to the renal effects of combined inhibition of 371 372 F. Tomoda et al Endopeptidase 24.15 and renal function these enzymes.…”

Section: Effects Of Hoe 140 In Conscious Rabbitsmentioning

confidence: 99%

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits

Tomoda

Lew

Smith

et al. 1996

British J Pharmacology

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1 We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2 Hoe 140 (0.1 mg kg-', i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney.3 Combined inhibition of ACE (captopril; 0.25 mg kg-' plus 0.2 mg kg-'h-') and EP 24.11 (SCH 39370; 3 mg kg-' plus 3 mg kg-'h-') was followed by a sustained reduction in arterial pressure (-6+ 2 mmHg) and increase in heart rate (35+7 beats min-'). There was a small increase in renal blood flow (by 6.5+3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-', i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects.4 When EP 24.15 was inhibited with N-[l-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB; 5 mg kg-' plus 3 mg kg-'h-', i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5 We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.

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“…VPIs simultaneously inhibit ACE and NEP, thereby acting to decrease circulating levels of vasoconstrictor effector molecules such as angiotensin II (AII) as well as increasing the levels of vasodilatory agents such as atrial natriuretic peptide and bradykinin (BK) [12,13]. Previous research using the first of the VPIs, omapatrilat, has examined the beneficial effects on ameliorating developing clinical and experimental hypertension [14,15,16]. In addition, an increasing number of studies have explored these agents in models of non-diabetic renal disease [13,17,18].…”

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confidence: 99%

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

et al. 2003

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Aims. Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Methods. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg −1 · day −1 ) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg −1 ·day −1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor β, β-inducible geneh3 and nephrin were also quantitated.Results. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFβ and βig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. Conclusion/Interpretation. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease. [Diabetologia (2003) 46:961-971]

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Dual Inhibition of Angiotensin-Converting Enzyme and Neutral Endopeptidase in Rats with Hypertension

Cited by 61 publications

References 0 publications

Phosphorus‐containing peptides as mixed inhibitors of endopeptidase 3.4.24.15 and 3.4.24.16: effect on neurotensin degradation in vitro and in vivo

Phosphorus‐containing peptides as mixed inhibitors of endopeptidase 3.4.24.15 and 3.4.24.16: effect on neurotensin degradation in vitro and in vivo

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

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