Renin-angiotensin aldosterone profile before and after angiotensin-converting enzyme-inhibitor administration in dogs with angiotensin-converting enzyme gene polymorphism

Abstract

Background: An angiotensin-converting enzyme (ACE) gene polymorphism occurs in dogs; however, functional importance is not well studied.

Hypothesis: We hypothesized that dogs with the polymorphism would show alternative renin-angiotensin aldosterone system (RAAS) pathway activation and classical RAAS pathway suppression before and after ACE-inhibitor administration, as compared to dogs without the polymorphism that would show this pattern only after ACE-inhibitor administration.

Animals: Twenty-one dogs with mitral valve disease that were genotyped for the ACE gene polymorphism.

Methods: This retrospective study utilized stored samples from 8 ACE gene polymorphism-negative (PN) dogs and 13 ACE gene polymorphism-positive (PP) dogs before and after enalapril administration. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities. Results were compared before and after enalapril, and between groups.

Results: The classical RAAS pathway was suppressed and the alternative RAAS pathway was enhanced for both genotypes after administration of enalapril, with no differences before enalapril administration. Aldosterone breakthrough occurred in both PN (38%) and PP (54%) dogs despite angiotensin II suppression. Aldosterone was significantly higher (P = .02) in ACE gene PP dogs (median, 92.17 pM; IQR, 21.85-184.70) compared to ACE gene PN dogs (median, 15.91 pM; IQR, <15.00-33.92) after enalapril.

Conclusions and clinical importance: The ACE gene polymorphism did not alter baseline RAAS activity. Aldosterone breatkthrough in some dogs suggests nonangiotensin mediated aldosterone production that might be negatively influenced by genotype. These results support the use of aldosterone receptor antagonists with ACE-inhibitors when RAAS inhibition is indicated for dogs, especially those positive for the ACE gene polymorphism.

Keywords: ACE-inhibitor; enalapril; genotype; pharmacogenetic; pharmacogenomic.

Figure 1

Renin‐angiotensin aldosterone system graphs in 8 control dogs that were negative for the ACE polymorphism and 13 dogs that were positive for the ACE polymorphism. Median values (pM) for each of the angiotensin metabolites and aldosterone are shown underneath each group before (pre) and after (post) enalapril. The size of the ball is proportional to the value. Values below the lower limit of quantification are shown as < the lowest reported value for each assay. Ang I, Angiotensin 1; Ang 1‐7, Angiotensin 1‐7; Ang II, Angiotensin II; Ang III, Angiotensin III; Ang 1‐5, Angiotensin 1‐5; Ang IV, Angiotensin IV; Aldo, Aldosterone; AT1R, Angiotensin II Receptor Type I; ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; AP, aminopeptidase; NEP, neprilysin

Figure 2

The percent increase in aldosterone after enalapril for dogs demonstrating aldosterone breakthrough was greater for ACE gene polymorphism positive dogs (PP) compared to ACE gene polymorphism negative dogs (PN) (P = .02)