Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/197183
Type: Artigo de periódico
Title: Pharmacokinetics And Pharmacodynamics Of A Nitric Oxide-releasing Derivative Of Enalapril In Male Beagles.
Author: Okuyama, Cristina E
Mendes, Gustavo Duarte
Faro, Renato
Rezende, Vinicius M
Lagos, Rodolfo Monaco
Astigarraga, Rafael E B
Antunes, Edson
De Nucci, Gilberto
Abstract: 1. 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. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/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). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.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. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-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. 5. 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.
Subject: Angiotensin-converting Enzyme Inhibitors
Animals
Area Under Curve
Blood Pressure
Chromatography, Liquid
Dogs
Dose-response Relationship, Drug
Enalapril
Enalaprilat
Enzyme Inhibitors
Half-life
Heart Rate
Inhibitory Concentration 50
Injections, Intravenous
Male
Molecular Structure
Ng-nitroarginine Methyl Ester
Nitric Oxide Donors
Tandem Mass Spectrometry
Time Factors
Rights: fechado
Identifier DOI: 10.1111/j.1440-1681.2007.04559.x
Address: http://www.ncbi.nlm.nih.gov/pubmed/17324140
Date Issue: 2007
Appears in Collections:Unicamp - Artigos e Outros Documentos

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