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Effect of endopeptidase 24.11 inhibition in conscious cardiomyopathic hamsters

GJ Smits, DE McGraw, AJ Trapani and EB Blaine

Searle Research and Development, St. Louis, Missouri.

An elevated plasma concentration of atrial natriuretic peptide (ANP) is characteristic of congestive heart failure (CHF) in both humans and animals. One strategy for facilitating the biological actions of this circulating hormone is to inhibit its metabolism. Neutral endopeptidase 24.11, an enzyme known to degrade ANP, has been implicated in the metabolic clearance of this hormone. Inhibition of endopeptidase 24.11 may produce increases in the local concentrations of ANP in organs rich in the enzyme, such as the kidney, thereby enhancing local actions, e.g. natriuresis. Exogenous administration of ANP to CHF patients produces limited natriuresis, perhaps because of the associated fall in arterial pressure. This approach of blocking endopeptidase 24.11 activity in CHF could offset the general effects of exogenous administration of ANP and result in enhanced natriuresis. We therefore undertook studies to determine if thiorphan, an endopeptidase 24.11 inhibitor, would increase circulating ANP levels and enhance natriuresis in conscious cardiomyopathic hamsters with CHF. Cardiomyopathic hamsters had significantly lower (P less than .05) basal mean arterial pressures in comparison to normal hamsters (90 +/- 2 vs. 135 +/- 3 mm Hg). Treatment with thiorphan (10 mg/kg i.v. bolus followed by 10 mg/kg/hr i.v. infusion) did not change arterial pressure in either group and produced a 3-fold increase in urinary sodium excretion in the cardiomyopathic group but not in the normal hamsters. This natriuretic response in the cardiomyopathic hamsters was associated with a doubling of the plasma concentration of ANP. These results indicate that inhibition of endopeptidase 24.11 increases natriuresis and circulating ANP concentrations in this model of CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 254, Issue 1, pp. 176-179, 07/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




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