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

Abstract

Background: The pathophysiology of heart failure involves maladaptive angiotensin peptides (APs) and enzymes, including angiotensin 2 (AT2) and angiotensin converting enzyme (ACE), as well as recently described alternative components, such as angiotensin 1-7 (Ang1-7) and angiotensin converting enzyme 2 (ACE2). The relative effects of different neurohormonal-targeting drugs on balance of APs in dogs with heart disease are unknown. Hypothesis/Objectives: Plasma AP concentrations differ in dogs receiving angiotensin converting enzyme inhibitors (ACEIs) vs angiotensin receptor blockers (ARBs) and recombinant human ACE2 (rhACE2) will further increase these differences. Animals: Eight dogs with degenerative mitral valve disease (DMVD). Methods: Prospective open-label trial. Equilibrium concentrations of APs from plasma during PO ACEI treatment and then after 14 days of PO ARB treatment using telmisartan were measured using liquid chromatography-tandem mass spectroscopy before and after in vitro incubation with rhACE2. Results: Concentration of Ang1-7 was increased during ARB treatment (Ang1-7: 443 pg/mL; 95% confidence interval [CI] = 247-794 pg/mL) vs ACEI (Ang1-7: 182 pg/mL; 95% CI = 66.2-503 pg/mL; P =.01). Incubation with rhACE2 decreased traditional APs while increasing beneficial alternative APs, and Ang1-7 was significantly higher in the ARB + rhACE2 (880 pg/mL; 95% CI = 560-1383 pg/mL) vs ACEI + rhACE2 (455 pg/mL; 95% CI = 188-1104 pg/mL; P =.03) group. The most favorable theoretical AP profile was achieved in the ARB + rhACE2 group. Conclusions and Clinical Importance: The AP profile during telmisartan treatment is associated with higher plasma Ang1-7 as compared with during ACEI. This favorable shift is potentiated in vitro by combination of ARB + rhACE2. These data support potential AP-targeting strategies and drugs in dogs with DMVD.