Specific inhibitors of endopeptidase 24.11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo

Olins, Gillian M.; Krieter, Philip A.; Trapani, Angelo J.; Spear, Kerry L.; Bovy, Philippe R.

doi:10.1016/0303-7207(89)90131-7

Cited by 74 publications

(38 citation statements)

References 29 publications

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“…The vasoconstriction caused by thiorphan was not reversed by systemic ACE inhibition but was abolished by ET receptor antagonism. Our findings are unlikely to be due to other actions of these agents because both candoxatrilat 8,9,17 and thiorphan 52,53 are highly specific for NEP. Furthermore, the finding that two structurally independent inhibitors of NEP produce vasoconstriction strongly suggests that this is a class effect of NEP inhibition on human resistance vessels.…”

Section: Discussionmentioning

confidence: 59%

Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

et al. 1998

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Background-Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone. Methods and Results-Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12Ϯ2%; Pϭ0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (Pϭ0.6) after pretreatment with both placebo (13Ϯ1%, Pϭ0.006) and enalapril (17Ϯ6%, Pϭ0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ET A antagonist BQ-123 (100 nmol/min), and both combined.

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Section: Discussionmentioning

confidence: 59%

Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

et al. 1998

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“…For instance, this enzym~ efficiently hydrolyzcs atrial natriuretic peptide (ANP) in vitro [3][4][5], and the physiological importance of en. dopeptidas¢ ~,4,11 in ANP metabolism has bccn further shown by in rive studies in animals and man [6][7][8] in which administration of specific inhibitors of the en. zyme caused increases in circulating ANP concentration with a concomitant aulFnentation in its physiological actions such as diuresis and natriuresis.…”

Section: Introductionmentioning

confidence: 99%

Endothelin 1 hydrolysis by rat kidney membranes

et al. 1992

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HydrolyJi,= ol'¢ndoth=lil~ l by rat kidney membran~ ~ats invcJtiilated min~ a r¢'~r,~-phz~ HPLC and an autonutted I~s.pham protein re.qa~r. F_.ndothelin I w~,= hydrolyz~;d into four major fragments which w=m d=t~:ted by HPL¢, Pho.phoramidon, an inhibitor of neutral endo~ptid~t,c 24,1 l, almost =ompl=t~y supp~_~d_ the production of thr¢~ fralrnrntr,, but on= fralr, mcnt was not affcrt~ by tl'~ inhibitor, Anallais ofN-terminal ~quence.s of the d¢l~radation products revcal~ that the pho~phoramidon-~cmlitiv¢ fralmenta were s~=rated by cl¢~vai~ at th~ Seal-Lea" bond of endoth¢lin I that wa~ ideation| with it~ clcavall~ ~it¢ by purified rat ¢ndoi~ptida~ 24,1 I, reported previously. Th= phozphoramidon.in~miti,,~ frallrnent was produc~.d by cl~val~ at ~u~=Asp '', which was distinct from the sites by endopeptida~ 24,11, but ¢orRtponded to that by a phosphoramidon.in~ndtivc m©tallo-endop~ptidar,~ recently it, elated from rat kidney mcmbran¢~ by us [(1992) Eur. J. Bioch~m, 204, 547-552]. Kinetic determination o1" endothclin I hydroly~lis by the i~lat~ eaaym¢ yielded walu~ of ,~,,=71.5 aM and ka,. = 1.49 s "~' Siv[n~ a ratio of A'.,/E,~=2,O8 x tO' tC',M", The/f~ value wutl much hisher and th¢ L'.d/~. value wa,~ much lower than tho~t £or rat ~ndo~ptida~ 24, I 1 reportad previou,,ly, Thus, endop.ptidarm 24,11 app*ar,, to h>,drolyz~ ¢ndoth~lin I more ¢fficicntly than the iml~t=d enzyme dot~. Both enzymes may play phyr, iologir.al rol~ in the rn¢taboli~m ofendothelin I by rat kidney m~ntbrun~ in vivo,

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“…NEP cleaves ANF at the cys 105-phe 106 bond resulting in an inactive, ring-deleted structure (Kenny & Stephenson, 1988). Inhibition of NEP prevents this inactivation of ANF and so prolongs its biological availability (Olins et al, 1989). What evidence is there that this might be a useful therapeutic option?…”

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confidence: 99%

“…Various specific inhibitors of NEP have been described in the last few years including phosphoramidon (Lafferty et al, 1989), thiorphan (Olins et al, 1989), SQ 29,072 (Seymour et al, 1989), SCH 34,826 (Sybertz et al, 1989), UK 69,578 (Danilewicz et al, 1989), [(±) candoxatrilat] and related compounds. All have been shown in vitro to delay the breakdown of ANF.…”

mentioning

confidence: 99%