Enkephalinase (EC 3.4.24.11) inhibitors: Protection of endogenous ANF against inactivation and potential therapeutic applications

doi:10.1016/0024-3205(90)90192-T

Life Sciences

Volume 47, Issue 15, 1990, Pages 1279-1297

https://doi.org/10.1016/0024-3205(90)90192-T Get rights and content

Abstract

Atrial natriuretic factor (ANF) is a cardiac hormone exerting potent cardiovascular and renal effects but its poor intestinal absorption and rapid inactivation have prevented so far its therapeutic utilisation. However inhibition of endogenous ANF metabolism progressively emerges as a novel therapeutic approach in cardiovascular and renal disorders. The critical role played by enkephalinase (membrane metalloendopeptidase, EC 3.4.24.11) in ANF inactivation was deduced from the effects of inhibitors. These compounds not only protect partially exogenous ANF from hydrolysis by some tissue preparations $in vitro$ but also, $in vivo$ , they increase the half-life of the exogenous hormone in plasma and, even more markedly, its recovery in intact form in kidney, a major target organ. In addition, enkephalinase inhibitors increase by two- to three-fold the circulating level of endogenous ANF, even when the latter is already markedly elevated, such as in patients with chronic heart failure. Finally, enkephalinase inhibitors induce a series of ANF-like responses such as natriuresis, diuresis or increase in cGMP excretion which are attributable to the hormone. These pharmacological observations, as well as preliminary clinical trials, suggest that enkephalinase inhibitors may represent a novel class of therapeutic agents with potential applications in a congestive heart failure, essential hypertension and various sodium-retaining states.

References (141)

T. Inagami
J. Biol. Chem.
(1989)
J.C. Schwartz et al.
Life Sci.
(1981)
J.C. Schwartz et al.
Trends Pharmacol. Sci.
(1985)
F. Fuller et al.
J. Biol. Chem.
(1988)
K.K. Murthy et al.
Mol. Cell. Endocr.
(1989)
T.G. Yandle et al.
Life Sci.
(1986)
F. Marumo et al.
Biochem. Biophys. Res. Commun.
(1986)
T. Yandle et al.
Biochem. Biophys. Res. Commun.
(1987)
J. Tang et al.
Regulat. Peptides
(1984)
J.A. Koehn et al.
J. Biol. Chem.
(1987)

G.M. Olins et al.

Biochem. Biophys. Acta

(1987)

P. Bertrand et al.

Biochem. Pharmacol.

(1988)

I.Y. Sakharov et al.

Biochem. Biophys. Res. Commun.

(1988)

E.L. Rugg et al.

Biochem. Biophys. Res. Commun.

(1988)

M. Deschodt-Lanckman et al.

Neurochem. Int.

(1988)

G.R. Johnson et al.

J. Biol. Chem.

(1989)

T.W. Lebien et al.

Blood

(1989)

M.G. Spillantini et al.

Neuropeptides

(1986)

T.G. Yandle et al.

Peptides

(1989)

K.K. Murthy et al.

Peptides

(1986)

J.L. Sonnenberg et al.

Peptides

(1988)

A.A. Seymour et al.

Life Sci.

(1988)

J. Bralet et al.

Eur. J. Pharmacol.

(1990)

M. Shima et al.

Life Sci.

(1988)

M. Vogt-Schaden et al.

Biochem. Biophys. Res. Commun.

(1989)

B. Malfroy et al.

Biochem. Biophys. Res. Commun.

(1987)

B. Malfroy et al.

FEBS Lett.

(1988)

A. Devault et al.

J. Biol. Chem.

(1988)

R.C. Bateman et al.

J. Biol. Chem.

(1989)

B. Malfroy et al.

Biochem. Biophys. Res. Commun.

(1982)

B. Malfroy et al.

J. Biol. Chem.

(1984)

J.M. Lecomte et al.

Eur. J. Pharmacol.

(1990)

D.B. Northridge et al.

Lancet

(1989)

J.C. Danilewicz et al.

Biochem. Biophys. Res. Commun.

(1989)

G.M. Olins et al.

Mol. Cell. Endocr.

(1989)

C. Gros et al.

Eur. J. Pharmacol.

(1990)

I. Schechter et al.

Biochem. Biophys. Res. Commun.

(1967)

W.L. Scott et al.

Life Sci

(1985)

S. De La Baume et al.

Eur. J. Pharmacol.

(1988)

H. Pollard et al.

Eur. J. Pharmacol.

(1987)

P. Chaillet et al.

Eur. J. Pharmacol.

(1983)

S. De La Baume et al.

Neuroscience

(1983)

R. Matsas et al.

Neurosci.

(1986)

K.L. Goetz

Am. J. Physiol.

(1988)

R.E. Lang et al.

J. Hypertension

(1987)

A.E.G. Raine et al.

Clin. Sci.

(1989)

M. Cantin et al.

Endocr. Rev.

(1985)

J.H. Laragh

N. Engl. J. Med.

(1985)

E.G. Erdos et al.

FASEB J.

(1989)

J.C. Schwartz

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MinireviewEnkephalinase (EC 3.4.24.11) inhibitors: Protection of endogenous ANF against inactivation and potential therapeutic applications

Abstract

J. Biol. Chem.

Life Sci.

Trends Pharmacol. Sci.

J. Biol. Chem.

Mol. Cell. Endocr.

Life Sci.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Regulat. Peptides

J. Biol. Chem.

Biochem. Biophys. Acta

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Neurochem. Int.

J. Biol. Chem.

Blood

Neuropeptides

Peptides

Peptides

Peptides

Life Sci.

Eur. J. Pharmacol.

Life Sci.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Eur. J. Pharmacol.

Lancet

Biochem. Biophys. Res. Commun.

Mol. Cell. Endocr.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Life Sci

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuroscience

Neurosci.

Am. J. Physiol.

J. Hypertension

Clin. Sci.

Endocr. Rev.

N. Engl. J. Med.

FASEB J.

Minireview
Enkephalinase (EC 3.4.24.11) inhibitors: Protection of endogenous ANF against inactivation and potential therapeutic applications