The effect of enalapril on furosemide-activated renin-angiotensin-aldosterone system in healthy dogs

J Vet Pharmacol Ther. 2015 Oct;38(5):513-7. doi: 10.1111/jvp.12216. Epub 2015 Mar 15.


Studies in our laboratory have revealed that furosemide-induced RAAS activation, evaluated via the urine aldosterone-to-creatinine ratio (UAldo:C), was not attenuated by the coadministration of benazepril, while enalapril successfully suppressed amlodipine-induced urinary aldosterone excretion. This study was designed to evaluate the efficacy of enalapril in suppressing ACE activity and furosemide-induced circulating RAAS activation. Failure to do so would suggest that this failure may be a drug class effect. We hypothesized that enalapril would suppress ACE activity and furosemide-induced circulating RAAS activation. Sixteen healthy hound dogs. The effect of furosemide (2 mg/kg PO, q12 h; Group F) and furosemide plus enalapril (0.5 mg/kg PO, q12 h; Group FE) on circulating RAAS was determined by plasma ACE activity, 4-6 h post-treatment, and urinary A:C on days -1, -2, 1, 4, and 7. There was a significant increase in the average urine aldosterone-to-creatinine ratio (UAldo:C) after administration of furosemide (P < 0.05). Enalapril inhibited ACE activity (P < 0.0001) but did not significantly reduce aldosterone excretion. A significant (P < 0.05) increase in the UAldo:C was maintained for the 7 days of the study in both groups. Enalapril decreased plasma ACE activity; however, it did not suppress furosemide-induced RAAS activation, as determined by the UAldo:C. While enalapril blunts ACE activity, the absence of circulating RAAS suppression may be due to angiotensin II reactivation, alternative RAAS pathways, and furosemide overriding concurrent ACE inhibition, all indicating the existence of aldosterone breakthrough (ABT). Along with similar findings with benazepril, it appears that failure to suppress aldosterone suppression with furosemide stimulation may be a drug class effect. The discrepancy between the current data and the documented benefits of enalapril likely reflects the efficacy of this ACE inhibitor in suppressing tissue RAAS, variable population responsiveness to ACE-inhibition, and/or providing additional survival benefits, possibly through as yet unknown mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / urine
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Blood Pressure / drug effects
  • Creatinine / urine
  • Diuretics / pharmacology*
  • Dogs
  • Drug Interactions
  • Enalapril / pharmacology*
  • Furosemide / pharmacology*
  • Heart Rate / drug effects
  • Peptidyl-Dipeptidase A / blood
  • Renin-Angiotensin System / drug effects*


  • Angiotensin-Converting Enzyme Inhibitors
  • Diuretics
  • Aldosterone
  • Enalapril
  • Furosemide
  • Creatinine
  • Peptidyl-Dipeptidase A