title: Pharmacokinetics and pharmacodynamics of a nitric oxide-releasing derivative of enalapril in male beagles.
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.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), 13081-970 Campinas, São Paulo, Brazil. cris_okuyama@yahoo.com.br
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Okuyama
authors.forename: Gustavo Duarte
authors.initials: GD
authors.lastname: Mendes
authors.forename: Renato
authors.initials: R
authors.lastname: Faro
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Rezende
authors.forename: Rodolfo Monaco
authors.initials: RM
authors.lastname: Lagos
authors.forename: Rafael E B
authors.initials: RE
authors.lastname: Astigarraga
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.forename: Gilberto
authors.initials: G
authors.lastname: De Nucci
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002853:Chromatography, Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*; D015773:Enalaprilat / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; C485988:NCX 899; D020030:Nitric Oxide Donors; D004656:Enalapril; D015773:Enalaprilat; D019331:NG-Nitroarginine Methyl Ester