Phosphoramidon-sensitive conversion of big endothelin-1 and degradation of endothelin-1 in rat kidney.

Fujita, Kazumi; Matsumura, Yasuo; Kita, Satomi; Hisaki, Kazuhiro; Takaoka, Masanori; Morimoto, Shiro

doi:10.1161/01.hyp.24.2.227

Cited by 15 publications

(6 citation statements)

References 38 publications

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“…The inability of the chymase inhibitor, chymostatin (Hisaki et al , 1994), to prevent DAG accumulation in response to big ET‐1 in our study, indicates that chymase does not mediate an alternative pathway for big ET‐1 conversion to ET‐1 in the PT. The amount of ET‐1 present in the tissue following exposure to big ET‐1 is thought to be a measure of the functional conversion of big ET‐1 (Hisaki et al , 1994; Fujita et al , 1994). Accordingly, phosphoramidon abolished the accumulation of ET‐1 in lung and renal tissue following perfusion with big ET‐1 (Hisaki et al , 1994; Fujita et al , 1994).…”

Section: Discussionmentioning

confidence: 99%

“…The amount of ET‐1 present in the tissue following exposure to big ET‐1 is thought to be a measure of the functional conversion of big ET‐1 (Hisaki et al , 1994; Fujita et al , 1994). Accordingly, phosphoramidon abolished the accumulation of ET‐1 in lung and renal tissue following perfusion with big ET‐1 (Hisaki et al , 1994; Fujita et al , 1994). In the present study, inhibition of ECE was demonstrated by the reduction of tissue ET‐1 content, in cortical slices pretreated with phosphoramidon and incubated subsequently with big ET‐1, to the level observed in slices not exposed to big ET‐1.…”

Section: Discussionmentioning

confidence: 99%

“…After incubation the Hanks’ solution was removed and the slices were washed three times in ice‐cold PBS. ET‐1 was extracted from the cortical tissue according to a previously published protocol (Fujita et al , 1994). Briefly, the slices were homogenized for 2 min in 3 ml of ice‐cold chloroformmethanol (2:1) containing 1 mM N‐ethyl‐maleimide (NEM).…”

Section: Methodsmentioning

confidence: 99%

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The effect of big endothelin‐1 in the proximal tubule of the rat kidney

Beara-Lasić

Knotek

Čejvan

et al. 1997

British J Pharmacology

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1 An obligatory step in the biosynthesis of endothelin-1 (ET-1) is the conversion of its inactive precursor, big ET-1, into the mature form by the action of speci®c, phosphoramidon-sensitive, endothelin converting enzyme(s) (ECE). Disparate eects of big ET-1 and ET-1 on renal tubule function suggest that big ET-1 might directly in¯uence renal tubule function. Therefore, the role of the enzymatic conversion of big ET-1 into ET-1 in eliciting the functional response (generation of 1,2-diacylglycerol) to big ET-1 was studied in the rat proximal tubules. 2 In renal cortical slices incubated with big ET-1, pretreatment with phosphoramidon (an ECE inhibitor) reduced tissue immunoreactive ET-1 to a level similar to that of cortical tissue not exposed to big ET-1. This con®rms the presence and eectiveness of ECE inhibition by phosphoramidon. 3 In freshly isolated proximal tubule cells, big ET-1 stimulated the generation of 1,2-diacylglycerol (DAG) in a time-and dose-dependent manner. Neither phosphoramidon nor chymostatin, a chymase inhibitor, in¯uenced the generation of DAG evoked by big ET-1. 4 Big ET-1-dependent synthesis of DAG was found in the brush-border membrane. It was unaected by BQ123, an ET A receptor antagonist, but was blocked by bosentan, an ET A,B -nonselective endothelin receptor antagonist. 5 These results suggest that the proximal tubule is a site for the direct eect of big ET-1 in the rat kidney. The eect of big ET-1 is con®ned to the brush-border membrane of the proximal tubule, which may be the site of big ET-1-sensitive receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The effect of big endothelin‐1 in the proximal tubule of the rat kidney

Beara-Lasić

Knotek

Čejvan

et al. 1997

British J Pharmacology

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“…15 Phosphoramidon is not entirely specific for NEP because, at high concentrations, it may also inhibit endothelin-converting enzyme. 18 Therefore we tested the effect of the specific NEP inhibitor SCH 39370 17 on the formation of BK- (1-7). The results were very similar to those obtained with phosphoramidon.…”

Section: Inhibition Of Kallidin and Bradykinin Degradation By Enzyme mentioning

confidence: 99%

Kallidin- and Bradykinin-Degrading Pathways in Human Heart

et al. 1999

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Background-Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue. Methods and Results-Cardiac membranes were prepared from the left ventricles of normal (nϭ5) and failing (nϭ10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M-like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal. Conclusions-The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart. (Circulation. 1999;99:1984-1990.)

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“…14,15 It follows that ET activity might be modified by local synthesis and/or degradation. Indeed, many tissues have both the synthetic and degradation machinery for ET-1 including kidneys, 16 suggesting local production and degradation of ET-1 that modulates tissue function in an autocrine/paracrine manner (see below).…”

Section: Overview Of Et Biologymentioning

confidence: 99%

Regulation of kidney acid excretion by endothelins

Wesson

2006

Kidney International

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Endothelin (ET) is a potent vasoconstrictor that is now known to modulate kidney tubule transport, including kidney tubule acidification. Animals undergoing an acid challenge to systemic acid-base status and with some models of chronic metabolic acidosis have increased kidney ET production. Increased ET production/activity contributes to enhanced kidney tubule acidification that facilitates kidney acid excretion in response to an acid challenge to systemic acid-base status. The data to date support a physiologic role for ET in mediating enhanced kidney acidification in response to acid challenges, but do not support an ET role in maintaining kidney tubule acidification in control, non-acid-challenged states. ET increases acidification in both the proximal and distal nephron and appears to exert its effects both directly and indirectly, the latter through modulating the levels and/or activity or other mediators of kidney tubule acidification. ET also contributes to enhanced kidney acidification in some pathophysiologic states and might contribute to some untoward outcomes associated with these conditions. Whether ET should be a therapeutic target in treating and/or preventing some of these untoward outcomes remains an open question. This review supports continued research into the physiologic and possibly pathophysiologic role of ET in settings of increased kidney tubule acidification.

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Phosphoramidon-sensitive conversion of big endothelin-1 and degradation of endothelin-1 in rat kidney.

Cited by 15 publications

References 38 publications

The effect of big endothelin‐1 in the proximal tubule of the rat kidney

The effect of big endothelin‐1 in the proximal tubule of the rat kidney

Kallidin- and Bradykinin-Degrading Pathways in Human Heart

Regulation of kidney acid excretion by endothelins

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