Acute hypotensive responses to peptide inhibitors of renin in conscious monkeys: an effect on blood pressure independent of plasma renin inhibition

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In order to investigate the hypotensive mechanisms of action of peptide renin inhibitors, blood pressure responses to five renin inhibitors were compared with those to the angiotensin converting enzyme inhibitor, enalaprilat, in conscious African green and rhesus monkeys. (3S-4S)-4-amino-5-cyclohexyl-3-hydroxy pentanoic acid (ACHPA)-containing renin inhibitory peptide (ACRIP) and enalaprilat both decreased blood pressure in euvolemic and volume-depleted African green monkeys. However, while a maximum dose of enalaprilat reduced blood pressure to 80 ± 4 and 56 ± 4 mmHg in the euvolemic and volume-depleted monkeys, respectively, ACRIP lowered pressure to life-threatening levels (< 40 mmHg) under both conditions. The relative potencies of ACRIP and four other renin inhibitors for inhibiting in vitro plasma renin activity (PRA; IC50) were compared with their potencies in reducing blood pressure by 15mmHg (ED 15mmHg) and lowering blood pressure more than enalaprilat in volume-depleted rhesus monkeys. All renin inhibitors lowered blood pressure significantly beyond the maximal response to enalaprilat. Despite a significant correlation (r=0.99, p <0.05) between the in vitro PRA inhibitory potency and the in vivo ED 15mmHg, doses which lowered blood pressure beyond the maximal responses to enalaprilat were not significantly correlated (r=0.53, p >0.05) with the in vitro PRA IC50 values. Furthermore, the profound depressor responses to renin inhibitors in rhesus monkeys were accompanied by increases in the heart rate and decreases in pulse pressure. These data demonstrate that peptide renin inhibitors can elicit blood pressure reductions by a plasma renin-dependent as well as a plasma renin-independent mechanism. Therefore, studies designed to investigate the antihypertensive efficacy of renin inhibitors may overestimate the renin-dependent hypotensive activity of these peptides

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