Antihypertensive Activity During Inhibition of Neutral Endopeptidase and Angiotensin Converting Enzyme

Seymour, A A; Swerdel, Joel N.; Abboa-Offei, B E

doi:10.1097/00005344-199103000-00015

Cited by 96 publications

(52 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Seymour et al (1991) and Pham et al (1993) both found greater antihypertensive effects of NEP inhibition when given in combination with ACE inhibition, although the former study did not test for statistical interaction between the effects of the drugs, and, in the latter study, the enhancement was most apparent in the first 30 min after the onset of drug treatment, with little or no difference at the end of a 2-h recording period. Indeed, in a later study by Pham et al (1995) the fall in blood pressure with combined ACE and NEP inhibition tended to be less than the expected sum of the individual effects, although, statistically, the antihypertensive effects of combined treatment did not differ from those of ACE alone.…”

Section: Discussionmentioning

confidence: 92%

“…To our knowledge, this is the first study to examine any possible interaction between the cardiovascular effects of angiotensin AT 1 receptor antagonism (with losartan) and NEP inhibition (with candoxatrilat or UK-489,329) in an in vivo setting. The experiments were performed in conscious SHR-a model that generally shows little or no hypotensive response to NEP inhibition (Koepke et al, 1990;Sybertz et al, 1990;Seymour et al, 1991;Pham et al, 1993Pham et al, , 1995Sala et al, 1994;Tikkanen et al, 1998) but robust and reproducible antihypertensive responses to inhibition of the renin-angiotensin system, either by ACE inhibition (for reviews, see Rubin and Antonaccio, 1980;Unger et al, 1990) or by AT 1 receptor antagonism (Wong et al, 1990;Bunkenburg et al, 1991;Li and Widdop, 1996). Overall, the results provide no evidence for interaction between the antihypertensive effects of AT 1 receptor antagonism and NEP inhibition, although the renal vasodilator effects of combined treatment were generally greater than the sum of the individual effects.…”

Section: Discussionmentioning

confidence: 99%

“…1), with or without concomitant administration of a low dose of the angiotensin receptor antagonist losartan, in conscious, spontaneously hypertensive rats (SHR). We chose this model because it is reported to be relatively resistant to the antihypertensive effects of NEP inhibition (Koepke et al, 1990;Sybertz et al, 1990;Seymour et al, 1991;Pham et al, 1993Pham et al, , 1995Sala et al, 1994;Tikkanen et al, 1998) but susceptible to the effects of inhibition of the reninangiotensin system, either by ACE inhibition (for reviews, see Rubin and Antonaccio, 1980;Unger et al, 1990) or by AT 1 receptor antagonism (Wong et al, 1990;Bunkenburg et al, 1991;Li and Widdop, 1996).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Gardiner

March²,

Kemp³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

We tested the hypothesis that angiotensin (AT 1 ) receptor antagonism (with losartan) would enhance the cardiovascular actions of neutral endopeptidase (NEP) inhibition [with candoxatrilat or (2S)-2-{[1-({[(1S)-1-carboxy-2-(5-phenyl-1,3-oxazol-2-yl)ethyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (UK-489,329)] in conscious spontaneously hypertensive rats (SHR). Four-day continuous intravenous infusion of candoxatrilat (1.9 g kg Ϫ1 min Ϫ1 ) or UK-489,329 (0.15 g kg Ϫ1 min Ϫ1 ) had no significant cardiovascular effects, whereas candoxatrilat (6.4 g kg Ϫ1 min Ϫ1 ) had a modest antihypertensive effect (Ϫ10.9 mm Hg on day 4) but no significant sustained effects on regional hemodynamics. Losartan caused a fall in blood pressure (maximum Ϫ29.2 mm Hg on day 4) that was associated with renal, mesenteric, and, to a lesser extent, hindquarters vasodilatation. The combination of losartan with either dose of candoxatrilat had no greater antihypertensive or vasodilator effects than losartan alone, with the exception of the increase in renal vascular conductance, which was greater with the combination of the drugs than with either drug alone (significant only in the lower dose study). Losartan combined with UK-489,329 showed a greater antihypertensive effect than losartan alone (Ϫ14.6 mm Hg greater on day 4), although the effects of the combination were not significantly greater than the sum of the effects of both agents administered separately. However, losartan combined with UK-489,329 caused increases in renal and hindquarters vascular conductance that were significantly greater with the combination than with either agent given alone. Thus, in conscious SHR, the renin-angiotensin system may act to oppose a vasodilator action of NEP inhibition, particularly in the renal vascular bed.Neutral endopeptidase 24.11 (NEP) is a zinc metalloprotease responsible for the breakdown of a number of short linear or cyclic peptides, such as the natriuretic peptides, bradykinin, angiotensin II, and endothelin. Other members of the zinc metalloprotease family that may be involved in the metabolism of biologically active peptides include endothelin-converting enzyme and soluble secreted endopeptidase (SEP) (Ikeda et al., 1999). Although NEP inhibitors were developed as antihypertensive agents, their effectiveness has turned out to be limited, probably because of their short half-life in the circulation, together with the fact that the breakdown of not only vasodilator/natriuretic peptides, but also vasoconstrictor peptides, such as angiotensin II and endothelin, is reduced (Richards et al., 1993;McDowell et al., 1997). In fact, some studies have found predominant vasoconstrictor effects of NEP inhibition in humans (Ferro et al., 1998). In animal studies, NEP inhibition with, for example, candoxatrilat, has only consistently been shown to exert antihypertensive effects in salt-sensitive models of hypertension (Shepperson et al., 1991;Hirata et al., 1994), and in human essential hypertension, candoxatril is reported to ha...

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Gardiner

March²,

Kemp³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The first metalloprotease inhibitors had the inconvenience of low potency, short-acting effect and limited bioavailability [75,76]. Omapatrilat however, shows long-lasting action (24 h effect after one oral administration) in both experimental and human studies.…”

Section: Combined Ace and Nep Inhibitionmentioning

confidence: 99%

Vasopeptidase inhibitors: will they have a role in clinical practice?

Worthley¹,

Corti²,

Worthley³

2003

Brit J Clinical Pharma

View full text Add to dashboard Cite

The human cardiovascular system is regulated by haemodynamic, neurohumoral and structural mechanisms. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances, and in the modulation of blood cell adhesion. Although the neurohormonal systems are essential in vascular homeostasis, they become maladaptive in conditions such as hypertension, coronary disease and heart failure.The clinical success of blocking the renin-angiotensin system by angiotensin converting enzyme (ACE)-inhibitors and the sympathetic nerve system by b -blockers demonstrates the importance of neurohumoral blockade. The inadequate effect of angiotensin converting enzyme (ACE) or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure, and the promising effect seen after their combination, led to the development of drugs that simultaneously inhibit both enzyme systems.Neutral endopeptidase, like ACE, is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for degradation of natriuretic peptides. The natriuretic peptide system can be viewed as the endogenous inhibitor of the renin angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors therefore represent a new and attractive therapeutic strategy for the treatment of cardiovascular disease. The ability to add incremental benefit over already proven therapy, with an acceptable side-effect profile however, is questionable in this new class of agents.

show abstract

“…The role of these agents in heart failure is of interest and remains to be fully assessed, although may be eclipsed by more encouraging data with angiotensin converting enzyme inhibitors (The SOLVD investigators, 1991). However, there is some current interest in compounds with combined actions to inhibit both angiotensin converting enzyme and NEP, and these may prove to be potent hypotensive and natriuretic agents (Seymour et al, 1991). Reports of the effects of such compounds in experimental animals and man will be awaited with interest.…”

mentioning

confidence: 99%

Therapeutic use of atrial natriuretic factor.

Connell

Jardine

Northridge

1992

Brit J Clinical Pharma

View full text Add to dashboard Cite

Antihypertensive Activity During Inhibition of Neutral Endopeptidase and Angiotensin Converting Enzyme

Cited by 96 publications

References 0 publications

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Vasopeptidase inhibitors: will they have a role in clinical practice?

Therapeutic use of atrial natriuretic factor.

Contact Info

Product

Resources

About

Antihypertensive Activity During Inhibition of Neutral Endopeptidase and Angiotensin Converting Enzyme

Cited by 96 publications

References 0 publications

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT1) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT1) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Vasopeptidase inhibitors: will they have a role in clinical practice?

Therapeutic use of atrial natriuretic factor.

Contact Info

Product

Resources

About

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats