Sustained Reduction in Blood Pressure During Chronic Administration of a Renin Inhibitor to Normotensive Marmosets

In this study, the hypotensive efficacy of a renin inhibitor was investigated during chronic administration. The renin inhibitor CGP 29,287 was administered by continuous intraperitoneal infusion with osmotic mini-pumps to normotensive marmosets fed a low-sodium diet. Marmosets received a dose of 0.3 (n = 5), 3.0 (n = 5), or 30 (n = 6) mg/kg/day for 14 days. Blood pressure (BP) and heart rate (HR) were measured in conscious animals by the tail-cuff method. Plasma renin activity (PRA) was reduced by 68% and 84%, respectively, by the 0.3 and 3.0 mg/kg/day doses. However, these doses had no significant effect on BP. Plasma-renin activity was reduced by 93% after 2 days of administration of the 30 mg/kg/day dose, and BP was significantly reduced (-24 +/- 4 mm Hg). After 14 days, PRA had recovered to pretreatment levels, but the hypotensive response persisted (-20 +/- 3 mm Hg). Despite the fall in BP, HR was not increased (292 +/- 22, 283 +/- 16, and 267 +/- 8 beats/min on days 0, 2, and 14, respectively). These findings indicate that, after 2 days of continuous administration, a dose of CGP 29,287 that induces almost complete inhibition of PRA is required to induce a significant fall in BP. Although there is subsequent recovery of PRA, the hypotensive response persists for 14 days. Thus, after chronic administration, the hypotensive efficacy of this renin inhibitor does not correlate with the degree of inhibition of PRA. However, these results indicate that renin inhibitors are effective hypotensive agents after chronic administration.