Function of phosphoramidon as an endothelin converting enzyme inhibitor

2018-08-18

Introduction 

Phosphoramidon is a kind of thermolysin inhibitor isolated from a culture filtrate of streptomyces. It has proved that phosphoramidon can inhibit endothelin converting enzyme and inhibit the formation of endothelin in vivo and in vitro experiments.

Pharmacologic action

Recent studies have shown that the unspecific protease inhibitor phosphoramidon appreciably lowers intraperitoneal tumor growth in CC531 cells compared with the control group. These results support the hypothesis that the extracellular matrix represents a factor in tumor invasion and tumor growth, together with the regulation of proteases. Interference with the physiological balance in favor of inhibition of the proteases may have an effective therapeutic potential in the prevention of intraperitoneal tumor growth after laparoscopic interventions.

Function

The phosphoramidon can protect myocardium of experimental myocardial injury of rats. The mechanism may inhibit endothelin converting enzyme (ECE) and then to reduce the production of endothelins, resulting the overload of calcium. Besides, intranasal administration of phosphoramidon produces significantly elevated cerebral Aβ levels in wild-type mice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP and NEP2 also shows increased levels of Aβ40. These data indicate that other phosphoramidon-sensitive peptidases are degrading Aβ in NEP/NEP2-deficient mice, which can be used to simulate Alzheimer's disease and show that intranasal delivery of drugs can be used to model AD. And in animals administered phosphoramidon (0.25 mg/kg per min i.v.), the hypertensive effect of big endothelin-1 is markedly attenuated. The same dose of phosphoramidon doesn't have an impact on the endothelin-1-induced hypertensive effect.

Pharmacokinetics and metabolism

At 1h but not 3h, inhibition of the formation of immunoreactive (ir)-ET-1/3 (17-21) by a mixture of phosphoramidon (100 μm) is observed in homogenates prepared from the hypothalamus (29±4%, n= 3) or the medulla oblongata (28 ± 75, n = 3). Besides, when infused in SHRs at 10, 20, and 40 mg/kg/h, phosphoramidon lowers mean arterial pressure (MAP) by 9 ± 4, 31 ± 4, and 40 ± 4 mm Hg after 5 h, which is relevant to dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. Renal hypertensive rats infused phosphoramidon in conscious loweres MAP by 31 ± 9, 46 ± 8, and 54 ± 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively.

References:

1. T. D. Warner, G. P. Budzik, T. Matsumoto, J. A. Mitchell, U. Förstermann and F. Murad. Regional differences in endothelin converting enzyme activity in rat brain: inhibition by phosphoramidon and EDTA. Br. J. Pharmacol., 1992, 106(4), 948-952.

2. K. Kitagishi and K. Hiromi. Binding between thermolysin and its specific inhibitor, phosphoramidon. J. Biochem., 1984, 95(2), 529-534.

3. T. Komiyama, T. Aoyagi, T. Takeuchi and H. Umezawa. Inhibitory effects of phosphoramidon on neutral metalloendopeptidases and its application on affinity chromatography. Biochem. Biophys. Res. Commun., 1975, 65(1), 352-357.

4. M. Pross, H. Lippert, R. Mantke, S. Krüger, T. Günther, F. Marusch, W. Halangk and H. U. Schulz. A proteinase inhibitor decreases tumor growth in a laparoscopic rat model. Surg. Endosc., 2011, 15(8), 882-885.

5. L. R. Hanson, D. Hafez, A. L. Svitak, R. B. Burns, X. Li, W. H. Frey and R. A. Marr. Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice. J Mol. Neurosci., 2011, 43(3), 424-427.

6. E. G. McMahon, M. A. Palomo, M. A. Brown, S. R. Bertenshaw and J. S. Carter. Effect of phosphoramidon (endothelin converting enzyme inhibitor) and BQ-123 (endothelin receptor subtype A antagonist) on blood pressure in hypertensive rats. Am. J. Hypertens., 1993, 6(8), 667-673.

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