Abstract 429: Antihypertensive Efficacy of NCX 899, a Nitric Oxide-releasing Derivative of Enalapril
Recently, a variety of well known drugs have been modified to incorporate a NO-donating moiety. We postulate that the anti-hypertensive efficacy of angiotensin-converting enzyme (ACE) inhibitors such as enalapril could be improved by adding a NO-donor group to the parent molecule. The present study compared the blood pressure lowering effects of NCX 899 (NO-enalapril) vs. enalapril in conscious aged (9–10 month-old) male spontaneously hypertensive rats with telemetry devices. Rats were dosed orally (QD) for 7 consecutive days with equimolar doses of NCX 899 or enalapril (8 umoL/kg, n=13 rats per treatment). Early and late systolic blood pressure (SBP) responses after oral dosing were obtained by averaging values from hours 2– 6 after dosing and hours 20 –23 after dosing. On day 1, NCX 899 and enalapril lowered SBP similarly (−21±3 vs. –19±3 mmHg, respectively) within 2– 6 hours. In contrast, after 7 days of treatment, NCX 899 treated rats had statistically significant lower SBP values (34±2 vs. 25±3 mmHg) 2– 6 h post dosing. The BP lowering effect of NCX 899 was superior to the BP lowering effect of enalapril after chronic dosing and it was achieved at a similar degree of ACE inhibition (40±8 vs. 57±7 % inhibition, NCX 899 vs. Enalapril, respectively) and equivalent levels of plasma enalaprilat. Enhanced efficacy of NCX 899 was associated with a statistically significant increase of basal plasma nitrate/nitrate (NOx) levels (2-fold change up to 6h post dosing on day 7). Both NCX 899 and enalapril lowered blood pressure similarly between 7 and 24 hrs post dosing. These results suggest that sustained superior efficacy of NCX 899 (between 2– 6 hrs post dosing) compared to enalapril over chronic dosing is most likely due to NO release. They also suggest that intermittent exposure to NO donation from these compounds does not lead to tolerance or diminished BP lowering effects. NO-releasing derivatives of ACE inhibitors could provide better blood pressure control and additional benefits such as enhanced vascular, renal and cardiac protection.