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.

Effect of angiotensin receptor blockers and angiotensin converting enzyme 2 on plasma equilibrium angiotensin peptide concentrations in dogs with heart disease

“…These results increase our understanding of drug effects on the traditional APs, driven by ACE, while simultaneously offering insight into the counterbalancing alternative arm, driven by ACE2. Our study, along with others, 19,22,26 demonstrates that ACEI treatment in dogs with heart disease is associated with relatively low production of APs that are primarily dependent on ACE, particularly AT2, which is produced by cleavage of 2 amino acids from AT1. Our data expand our understanding of ACE production of Ang1‐7, which occurs by ACE‐mediated cleavage of 2 amino acids from Ang1‐9, and also of Ang1‐5, which is produced by cleavage of 2 amino acids from Ang1‐7.…”

Factors affecting the urinary aldosterone-to-creatinine ratio in healthy dogs and dogs with naturally occurring myxomatous mitral valve disease

“…The influence of breed on RAAS activity could be related to differences in genes encoding for RAAS components. Polymorphism of angiotensin-converting enzyme gene has been found in several breeds, including CKCS and Chihuahua, but it has been suggested that it could be more common in certain breeds [47][48][49]. Little is known about the effect of this polymorphism on RAAS components in dogs, but, as previously reported in humans [50], a recent study has found higher aldosterone levels and ABT incidence in MMVD dogs with ACE polymorphism after enalapril treatment and in presence of adequate ACE-A-II suppression, suggesting that this genotype could be involved in the upregulation of alternative pathways for aldosterone secretion [47].…”

“…Polymorphism of angiotensin-converting enzyme gene has been found in several breeds, including CKCS and Chihuahua, but it has been suggested that it could be more common in certain breeds [47][48][49]. Little is known about the effect of this polymorphism on RAAS components in dogs, but, as previously reported in humans [50], a recent study has found higher aldosterone levels and ABT incidence in MMVD dogs with ACE polymorphism after enalapril treatment and in presence of adequate ACE-A-II suppression, suggesting that this genotype could be involved in the upregulation of alternative pathways for aldosterone secretion [47]. Furthermore, polymorphism of genes encoding for angiotensinogen, A-II type 1 receptor, aldosterone synthase and chymase have been reported in humans and may also be present in dogs [51][52][53][54].…”

Prevalence of an angiotensin-converting enzyme gene variant in dogs

“…Inhibitors of ACE are used clinically to reduce the formation of angiotensin II, thereby mitigating these effects which contribute to cardiovascular and renal disease progression, fluid retention, and systemic hypertension [1,2]. Clinically effective RAAS suppression by ACE-inhibitors, however, is sometimes sub-optimal because of aldosterone breakthrough, non-ACE mediated angiotensin II formation, genetic variants affecting RAAS components, feedback mechanisms, and likely other unidentified factors [3][4][5][6][7]. The ACE gene intronic variant at canine chromosome 9:11507816:G > A has recently been shown to increase the magnitude of aldosterone breakthrough, despite adequate suppression of angiotensin II by ACEinhibitors [4].…”

“…Clinically effective RAAS suppression by ACE-inhibitors, however, is sometimes sub-optimal because of aldosterone breakthrough, non-ACE mediated angiotensin II formation, genetic variants affecting RAAS components, feedback mechanisms, and likely other unidentified factors [3][4][5][6][7]. The ACE gene intronic variant at canine chromosome 9:11507816:G > A has recently been shown to increase the magnitude of aldosterone breakthrough, despite adequate suppression of angiotensin II by ACEinhibitors [4]. Genotype influence on non-angiotensin mediated aldosterone production holds clinical implications for dogs with advanced heart disease in both disease expression and response to treatments, but the prevalence of this variant in the canine population is unknown.…”