Renal and Hormonal Effects of Chronic Inhibition of Neutral Endopeptidase (EC 3.4.24.11) in Normal Man

Abstract

1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC 3.4.24.11), which cleaves the cardiac hormone atrial natriuretic peptide, raises endogenous levels of the hormone. Short-term administration of inhibitors causes natriuresis and diuresis in normal and hypertensive subjects; we report here the effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg) given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a placebo-controlled cross-over study. 2. Candoxatril administration caused a transient natriuresis on day 1 of treatment, but this was not sustained, and cumulative sodium excretion at the end of the study was not altered by active therapy [1720 ± 40 versus 1734 ± 57 (placebo) mmol; means ± SEM]; exchangeable body sodium content was similarly unchanged. However, urinary cyclic GMP excretion was elevated throughout the active treatment phase when compared with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide could not be demonstrated, platelet atrial natriuretic peptide binding sites were reduced by active treatment [23 ± 3 versus 39 ± 4 (placebo) fmol/109; P <0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril treatment. After 10 days of therapy subjects were given incremental infusions of angiotensin II (2, 4 and 8 ng min−1 kg−1) followed by phenylephrine. Although active therapy had not altered basal plasma concentrations of active renin and angiotensin II, levels of angiotensin II during infusion of the octapeptide were higher during the active phase. The diastolic pressor response to angiotensin II was increased during candoxatril treatment, although this is likely to reflect the higher plasma levels of angiotensin II during infusion of the octapeptide. In contrast, the systolic and diastolic pressor responses to phenylephrine were reduced by active treatment. 5. In conclusion, chronic candoxatril administration increases urinary cyclic GMP excretion without causing sustained natriuresis; evidence of atrial natriuretic peptide receptor down regulation was seen. There were no sustained hormonal or haemodynamic changes during therapy. The increased levels of angiotensin II during its infusion in the presence of candoxatril may reflect the role of neutral endopeptidase in clearing angiotensin II from the circulation.