Prolonged inhibition of endopeptidase 24.11 in normal man

The renal, hormonal and haemodynamic effects of chronic (4 days) dosing with an inhibitor of endopeptidase EC 3.4.24.11 (UK 79300) were assessed in two groups, each of eight normal volunteers, receiving 25 mg every 12 h (group 1) or 100 mg every 12 h (group 2) of UK 79300 in double-blind, balanced-randomized, placebo-controlled, crossover studies. Group 2 (but not group 1) exhibited a significant transient natriuresis (P<0.01) and a consequent sustained negative cumulative sodium balance (70 21 mmol) which was established within 48 h and remained for the duration of dosing with UK 79300. Urine and plasma cyclic guanosine monophosphate (cGMP) levels rose significantly above placebo values (P<0.01 and P<0.001, respectively) in both groups and the effect was sustained throughout the dosing period. Plasma atrial natriuretic factor (ANF) was slightly enhanced by UK 79300 in group 1 (P< 0.05) but not significantly increased in group 2. Despite a significant increase in heart rate in both groups (P< 0.001) and of natriuresis in group 2, there was minimal evidence of renin-aldosterone activation in either group. trends towards lower systolic pressures, observed in both groups, did not attain statistical significance. These findings suggest chronic treatment with UK 79300 induces an increase in tissue ANF levels, with sustained enhancement of plasma and urine concentrations of ANF second messenger (cGMP) and increased heart rate.