Author: Gustavo Duarte Mendes ; Rodolfo Monaco Lagos ; Edson Antunes ; Gilberto De Nucci ; Rafael E B Astigarraga ; Vinicius M Rezende ; Renato Faro ; Cristina E Okuyama

SUMMARY

Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO‐releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated.

Dogs received either NCX899 (4 µmol/kg, i.v.) or enalapril (4 µmol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS).

In the NCX899 group, the area under the time‐course curve (AUC0−24h) was 29.18 ± 4.72, 229.37 ± 51.32 and 5159.23 ± 514.88 µg·h/L for the analytes nitro‐enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC0−24h was 704.53 ± 158.86 and 4149.27 ± 847.30 µg·h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin‐converting enzyme.

In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 0.1–10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect.

In conclusion, the present results showed that the NO‐releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.

01 Mar 2004·The FASEB JournalQ2 · BIOLOGY

A nitric oxide‐releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in hamsters with heart failure

Q2 · BIOLOGY

Article

Author: Dieterle, Thomas ; Peterson, Kirk L. ; Iwanaga, Yoshitaka ; Ross, John ; Soldato, Piero Del ; Ongini, Ennio ; Gu, Yusu ; Presotto, Cristina ; Condorelli, Gianluigi

Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Phase 1	-	Merck Sharp & Dohme Corp.	-
Hypertension	Phase 1	-	Nicox SA	-

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