Evidence for a direct vasoconstrictor effect of big endothelin-1 in the rat kidney

Salvati, Patricia; Dho, Luciano; Calabresi, Marcello; Rosa, Bruno; Patrono, Carlo

doi:10.1016/0014-2999(92)90712-d

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…One study suggested that big ET-1 has direct vasoconstrictor effects without conversion to ET-1 in the rat kidney. 31 Although our results do not exclude this possibility, most if not all of the pressor effect of big ET-1 in the kidney is attributed to ET-1 converted from big ET-1. Further studies should address the point of whether big ET-1 has an intrinsic direct vasoconstrictor effect in vivo.…”

Section: Discussioncontrasting

confidence: 38%

“…In addition, the absence (isolated kidney) or presence (in vivo) of extrarenal humoral or nervous influences may be involved in the above discrepancy. On the other hand, Salvati et al 31 reported that phosphoramidon potentiates the renal vasoconstrictive effect of ET-1 in vivo. This result supports the hypothesis that NEP is responsible for the degradation of ET-1 in the kidney.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1994

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We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the pepride was 50-fold less than that of ET-1. The big ET-1 (2xlO" 8 mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10~4 mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect The effect of kelatorphan (10" 4 mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with phosphoramidon. When ET-1 was exog-E ndothelin-1 (ET-1) is a potent vasoconstrictor peptide originally isolated from the supernatant of cultured porcine aortic endothelial cells.1 Sequence analysis of cDNA encoding ET-1 suggested that ET-1 is produced from an intermediate form termed big ET-1 by a specific endothelin-converting enzyme (ECE).1 Several candidates for ECE have been identified in cultured endothelial cells and tissue homogenates, and attention has focused on a neutral metalloproteinase. 2 We and other investigators consider that phosphoramidon-sensitive metalloproteinase is the most plausible candidate for ECE in endothelial cells 34 and other tissues. 56Big ET-1 is a weaker vasoconstrictor than ET-1 in vitro by two orders of magnitude but has a pressor effect comparable to that of ET-1 in vivo.7 Phosphoramidon was seen to markedly suppress big ET-1-induced hypertensive effects without affecting the response to ET-1 in anesthetized rats. 89 These findings suggest that phosphoramidon-sensitive conversion of big ET-1 to mature ET-1 is essential for the expression of full biological activities in vivo.ET-1 has diverse biological activities in the kidney.10 l5 Administration of ET-1 into the renal artery in intact animals induces intense renal vasoconstricReceived December 14, 1993; accepted in revised form May 16, 1994.From the Department of Pharmacology, Osaka (Japan) University of Pharmaceutical Sciences.Reprint requests to S. Morimoto, PhD, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 2-10-65 Kawai, Matsubara, Osaka 580, Japan.© 1994 American Heart Association, Inc.enousry added to the perfusate, phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin...

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Section: Discussioncontrasting

confidence: 38%

Section: Discussionmentioning

confidence: 99%

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

et al. 1994

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“…First, since it is known that ET-l can be metabolized by brush-border endopeptidases (Abassi et al, 1992;Asaad et al, 1993), it is possible that the additional 11 amino acids on big ET-1 could protect it from proteolytic degradation thus facilitating access of mature ET-1 to tubular endothelin receptors. Also, there are a few studies that suggest a direct effect of big ET-1, producing certain haemodynamic effects independent of conversion to ET-1 (Auguet et al, 1992;Salvati et al, 1992). Since the ETB receptor has been linked to endothelium-dependent vasodilatation (Warner et al, 1989), we can hypothesize that big ET-1 may produce ETB receptor mediated increases in medullary blood flow as a mechanism for producing diuresis and natriuresis.…”

Section: Resultsmentioning

confidence: 99%

ET_A receptor‐mediated responses to endothelin‐1 and big endothelin‐1 in the rat kidney

Pollock

Opgenorth

1994

British J Pharmacology

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1 Renal clearance experiments were conducted in anaesthetized Sprague-Dawley rats to determine the effect of the ETA receptor antagonist, BQ-123, on the renal haemodynamic response to endothelin-1 (ET-1) and its precursor, big endothelin-1 (big ET-1) at doses that produce an equivalent degree of renal vasoconstriction.2 Infusion of either big ET-1 at 100 pmol kg-min' or ET-1 at 12pmolkg-'min'1 for 60min produced almost identical decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Big ET-1 produced an increase in mean arterial pressure (MAP) that was significantly larger than the increase produced by ET-1. 3 Co-infusion with BQ-123 (0.1 mg kg-' min-') prevented the rise in MAP produced by big ET-1 and completely blocked the renal response. Similarly, BQ-123 inhibited both the increase in MAP and the decrease in RPF and GFR produced by ET-1. 4 Big ET-1 but not ET-1, produced a significant increase in water and sodium excretion. BQ-123 had no effect on the diuretic and natriuretic response to big ET-1 consistent with possible ETB-mediated inhibition of tubular reabsorption. 5 We have previously shown that at higher doses of ET-1, BQ-123 was unable to inhibit the renal vasoconstrictor response despite blockade of the pressor response. Taken together, these results indicate that ET-1 activates primarily ETA receptors at moderately low doses to produce renal vasoconstriction while higher doses also involve non-ETA receptors. 6 Since ET-l has a similar binding affinity for both ETA and ETB receptors, we suggest that there may be a third type of ET-1 receptor in the rat kidney with lower affinity for ET-1 that is coupled to a vasoconstrictor mechanism.

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“…We suggest that conformation of the processing site, rather then specific composition of residues, defines cleavage specificity by the ECE. Open questions that deserve further investigation are whether big ET-1 itself has physiological effects not dependent on its convertion into ET-1 (24) and whether bioactive peptides may arise from processing of proET-1 along the regulated pathway of secretion.…”

Section: Discussionmentioning

confidence: 99%

In vivo expression of mutant preproendothelins: hierarchy of processing events but no strict requirement of Trp-Val at the processing site.

Fabbrini

Vitale

Nitti

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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Endothelin-1 (ET-1), a 21-residue vasoconstrictor peptide, originates in human cells from a 212-amino acid precursor (preproET-1). Big ET-1, an intermediate form of 38 amino acids, is generated by cleavage at basic-pair residues of proET-1, while a specific "ET-converting enzyme" was proposed to process the unusual Trp-Val site at positions 21 and 22 of big ET-1. We have previously shown that expression of synthetic RNA encoding human preproET-1 in Xenopus oocytes results in secretion of putative ET-1 and big ET-1. Here, to further dissect the processing pathway of preproET-1, we designed and expressed in oocytes a set of preproET-1 mutants. Four mutants affecting the Trp-Val site always originated putative ET-1(s) at levels comparable to the wild type, suggesting that there is only a conformational requirement for cleavage at this site. An Arg --Ile mutation at the basic-pair site after the C terminus of big ET-1 fully inhibited the formation of both big ET-1 and ET-1, indicating that processing at this site is an early event and that big ET-1 is an obligate intermediate for the synthesis of ET-1 in vivo. Also, a truncated mutant bearing a stop codon after the C terminus of the big ET-1 sequence was totally stable and further processed into mature big ET-1 and ET-1, indicating that the second part of the precursor is not necessary for maturation.The 21-residue vasoconstrictor peptide human endothelin-1 (ET-1), like many growth factors and peptide hormones, is first synthesized as a larger inactive precursor (preproET-1, see Fig. 1) (1). While ET-1 seems to exert a wide range of diverse biological activities (2), the 38-amino acid intermediate big ET-1 is at least 2 orders of magnitude less potent than ET-1 in contractile activity, and it is still not clear whether it plays some pathophysiologic role. Many efforts have been made to search for a specific endothelinconverting enzyme (ECE) responsible for the cleavage of the unusual Trp-Val site of big ET-1 as a key element in the regulation of ET-1 biosynthesis (3, 4). However, expression of human preproET-1 in Xenopus oocytes (5) or insect cells (6) results in constitutive secretion of peptides with immunological and biological characteristics of ET-1 and big ET-1.For further study of the processing events and molecular requirements leading to big ET-1 and ET-1 formation, we report expression of a set of mutated preproendothelins in Xenopus oocytes. We demonstrate that big ET-1 is a necessary intermediate in the formation of ET-1, whereas the second part of preproET-1 (after the C terminus of big ET-1) is not necessary for the synthesis of these two peptides.

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Evidence for a direct vasoconstrictor effect of big endothelin-1 in the rat kidney

Cited by 9 publications

References 28 publications

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

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

ET_A receptor‐mediated responses to endothelin‐1 and big endothelin‐1 in the rat kidney

In vivo expression of mutant preproendothelins: hierarchy of processing events but no strict requirement of Trp-Val at the processing site.

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Evidence for a direct vasoconstrictor effect of big endothelin-1 in the rat kidney

Cited by 9 publications

References 28 publications

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

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

ETA receptor‐mediated responses to endothelin‐1 and big endothelin‐1 in the rat kidney

In vivo expression of mutant preproendothelins: hierarchy of processing events but no strict requirement of Trp-Val at the processing site.

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ET_A receptor‐mediated responses to endothelin‐1 and big endothelin‐1 in the rat kidney