EFFECT OF INHIBITION OF ENDOPEPTIDASE 24.11 ON RESPONSES TO ANGIOTENSIN-II IN HUMAN VOLUNTEERS

The effects of endopeptidase 24.11 inhibition on angiotensin-induced changes in plasma angiotensin II, aldosterone, and atrial natriuretic factor concentrations and blood pressure were assessed in normal volunteers. Two groups, each consisting of eight normal volunteers, received stepwise infusions of angiotensin II (2, 4, and 8 ng/kg per minute) on day 5 of dose administration with 25 mg every 12 hours (group 1) or 100 mg every 12 hours (group 2) of an oral inhibitor of endopeptidase 24.11 (UK 79300, candoxatril) or placebo in balanced randomized, double-blind, placebo-controlled crossover studies. Both doses of candoxatril significantly enhanced achieved plasma angiotensin II concentrations during infusions (group 1,p<0.001; group 2, p<0.01; overall treatment effect for combined data, p<0.001). This effect was most pronounced at the highest dose of angiotensin II (treatment-time interaction, p<0.0001 for combined data) and tended to be more marked with the higher dose of candoxatril (treatment-group interaction, p=0.08). The pressor response to angiotensin II was clearly enhanced by the lower dose of candoxatril; peak systolic and diastolic pressures exceeded placebo values by approximately 10 mm Hg (p<0.001 and p<0.05 for systolic and diastolic pressures, respectively). This effect of candoxatril was absent in group 2, which (unlike group 1) had exhibited a modest natriuretic response (sustained cumulative negative sodium balance, -70 +/- 21 mmol; p<0.01) to the higher dose of inhibitor. Baseline plasma aldosterone concentrations and the incremental aldosterone response to angiotensin II infusions were not significantly altered by low-dose (group 1) candoxatril. Basal aldosterone levels were slightly enhanced by the higher dose of inhibitor (p<0.05), but the incremental response to angiotensin II infusions was unchanged. Pretreatment with candoxatril caused plasma atrial natriuretic factor to rise above baseline values during angiotensin infusions (p<0.001, combined data). Inhibition of endopeptidase 24.11 significantly reduced clearance of infused angiotensin II in association with an enhanced pressor response to exogenous angiotensin when the inhibitor was given in doses below natriuresis. For cases in which a sufficient inhibitor was administered to elicit natriuresis, pressor responses did not change despite augmented plasma angiotensin II. These data carry implications for the potential therapeutic use of endopeptidase inhibitors in high and low renin states.