We have investigated whether a chymostatin-sensitive enzyme, such as chymase, contributes to the production of vasoconstrictor endothelin peptides from exogenous big endothelin- 1 in endothelium-denuded human umbilical vein. Big endothelin-1 contracted veins with a pD2 = 7.75 +/- 0.08 (n = 23) and was five times less potent than endothelin-1 (pD2 = 8.43 +/- 0.11, n = 10). The selective endothelin-converting enzyme inhibitor, PD159790, (30 microM, n = 17) produced a significant (P < 0.005), threefold rightward shift of the big endothelin-1 concentration-response curve with no reduction in maximum response. A further shift was obtained with 100 microM PD159790 (n = 6), with a significant decrease in the maximum response from 84.0 +/- 5.3%KCl to 34.2 +/- 6.7%KCl (P < 0.005). Chymostatin (30 microM) had no effect on the big endothelin-1 response, however, the inhibitory effect of 100 microM chymostatin was significant (P < 0.005). Unlike PD159790, chymostatin did not significantly modify the maximum response to big endothelin-1. The combination of 30 microM PD159790 and 100 microM chymostatin was more effective than either inhibitor alone. Our data suggest a role for both endothelin-converting enzyme and a chymostatin-sensitive enzyme, such as chymase, in the conversion of big endothelin-1 to constrictor endothelin peptides in human umbilical vein smooth muscle. In cardiovascular diseases in which endothelin-converting enzyme activity is increased, inhibition of both enzymes may be required for effective therapeutic intervention.

01 Nov 2001·British Journal of PharmacologyQ2 · MEDICINE

Vasoconstrictor activity of novel endothelin peptide, ET‐1_{(1 – 31)}, in human mammary and coronary arteries in vitro

Q2 · MEDICINE

Article

Author: Anthony P Davenport ; Rhoda E Kuc ; Janet J Maguire

The ability of the putative chymase product of big endothelin‐1 (big ET‐1), ET‐1(1 – 31), to constrict isolated endothelium‐denuded preparations of human coronary and internal mammary artery was determined.

pD2 values in coronary and mammary artery respectively were 8.21±0.12 (n=14) and 8.55±0.11 (n=12) for ET‐1, 6.74±0.11 (n=16) and 7.10±0.08 (n=16) for ET‐1(1 – 31) and 6.92±0.10 (n=15) and 7.23±0.11 (n=12) for big ET‐1. ET‐1(1 – 31) was significantly less potent than ET‐1 (P<0.001, Student's t‐test) and equipotent with big ET‐1.

Vasoconstrictor responses to 100 – 700 nM ET‐1(1 – 31) were significantly (P<0.05, Student's paired t‐test) attenuated by the ETA antagonist PD156707 (100 nM).

There was no effect of the ECE inhibitor PD159790 (30 μM), the ECE/NEP inhibitor phosphoramidon (100 μM) or the serine protease inhibitor chymostatin (100 μM) on ET‐1(1 – 31) responses in either artery.

Radioimmunoassay detected significant levels of mature ET in the bathing medium of coronary (1.6±0.5 nM, n=14) and mammary (2.1±0.6 nM, n=14) arteries, suggesting that conversion of ET‐1(1 – 31) to ET‐1 contributed to the observed vasoconstriction.

ET‐1(1 – 31) competed for specific [125I]‐ET‐1 binding to ETA and ETB receptors in human left ventricle with a pooled KD of 71.6±7.0 nM (n=3).

Therefore, in human arteries the novel peptide ET‐1(1 – 31) mediated vasoconstriction via activation of the ETA receptor. The conversion of ET‐1(1 – 31) to ET‐1, by an as yet unidentified protease, must contribute wholly or partly to the observed constrictor response. Chymase generated ET‐1(1 – 31) may therefore represent an alternative precursor for ET‐1 production in the human vasculature.

British Journal of Pharmacology (2001) 134, 1360–1366; doi:10.1038/sj.bjp.0704384

01 Jan 2000·Journal of Cardiovascular Pharmacology

Inhibitor Potencies and Substrate Preference for Endothelin-Converting Enzyme-1 are Dramatically Affected by PH

Article

Author: Knapp, J ; Ahn, K ; Johnson, G D ; Fahnoe, D C

Phosphoramidon has been shown to inhibit endothelin-converting enzyme-1 (ECE-1) in a remarkably pH-dependent manner (Ahn et al. Arch Biochem Biophys 1998;359:258-68). In order to determine whether this dramatic pH-dependence is a general phenomenon of ECE-1, two structurally unrelated ECE-1 inhibitors, PD 069185 and CGS 31447, were tested for ECE-1 inhibition at various pH values. Our data indicate that the potencies of these ECE-1 inhibitors are also highly affected by pH. ECE-1 is known to have a very sharp activity optimum at neutral pH which is in marked contrast to the acidic pH optimum for ECE-2. However, our results show that the pH optimum for ECE-1 activity is highly substrate-dependent. ECE-1 hydrolyzes the small peptide hormones bradykinin and substance P with acidic pH optima of 5.6-5.8, which sharply contrasts the neutral pH optimum with big ET-1 as substrate. These data suggest that the substrate preference for ECE-1 is highly affected by pH and that this pH-dependence for substrate preference might be one way of controlling the specificity of the enzyme in vivo.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Discovery	US	Pfizer Inc.	-

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