Comprehensive characterization of the effect of mineralocorticoid receptor antagonism with spironolactone on the renin-angiotensin-aldosterone system in healthy dogs.

OBJECTIVE: To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs. ANIMALS: Ten healthy purpose-bred Beagle dogs. PROCEDURES: Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups. RESULTS: Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment. CONCLUSIONS: Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.

The classical and alternative circulating renin-angiotensin system in normal dogs and dogs with stage B1 and B2 myxomatous mitral valve disease.

BACKGROUND: The behavior of the comprehensive circulating renin-angiotensin system (RAS) in dogs with myxomatous mitral valve disease (MMVD) before to the onset of congestive heart failure remains largely unexplored. HYPOTHESIS/OBJECTIVES: The classical and alternative RAS activity and aldosterone concentrations will be significantly higher in dogs with American College of Veterinary Internal Medicine (ACVIM) stage B2 MMVD compared to normal dogs and dogs with ACVIM stage B1 MMVD. ANIMALS: One-hundred seventeen client-owned dogs (normal = 60; B1 = 31; B2 = 26). METHODS: Prospective observational study. Angiotensin peptides (AP) and aldosterone concentrations were measured using liquid chromatography and mass spectrometry. Angiotensin converting enzymes 1 and 2 (ACE, ACE2) and renin activity surrogates were calculated from AP concentrations. Equilibrium dialysis (ED) and immediate protease inhibition (PI) methods of AP quantification were compared in 14 healthy dogs. RESULTS: Core RAS activity and aldosterone concentrations did not differ among the 3 groups. However, the balance between the alternative and classical RAS differed, with dogs with stage B2 MMVD having significantly higher ACE2 activity surrogate (ACE2surr ) when compared to normal dogs (adjusted P = .02; ratio of medians for ACE2surr [B2:normal], 1.89; 95% confidence interval [CI]: 1.4-2.6). The ED and PI methods of AP quantification were highly correlated (AngI, r = .9, P < .0001; AngII, r = .8, P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Circulating alternative RAS activity, specifically the surrogate measure of ACE2 activity, was increased in dogs with stage B2 MMVD as compared to normal dogs. Equilibrium dialysis results are analogous to immediate protease inhibition in dogs.

Effects of short-term anti-inflammatory glucocorticoid treatment on clinicopathologic, echocardiographic, and hemodynamic variables in systemically healthy dogs.

OBJECTIVE To investigate mechanisms by which anti-inflammatory doses of orally administered intermediate-acting glucocorticoids (prednisone) could predispose dogs to progression of heart disease or congestive heart failure. ANIMALS 11 client-owned dogs with allergic dermatitis and 11 matched healthy control dogs. PROCEDURES Clinicopathologic, echocardiographic, and hemodynamic variables were measured. Dogs with allergic dermatitis then received prednisone (1 mg/kg, PO) once daily for 14 consecutive days beginning on day 0 (baseline), followed by a tapering and washout period; control dogs received no treatment. Measurements were repeated on days 7, 14, and 35. Linear mixed modeling was used to compare changes in variables across measurement points and between dog groups. RESULTS Prednisone administration caused no significant changes in serum sodium or potassium concentration, blood glucose concentration, or target echocardiographic variables. The change from baseline in systolic arterial blood pressure at day 7 was significantly greater in prednisone-treated dogs than in control dogs. Expected changes in hematologic and serum biochemical values with prednisone administration (neutrophilia, eosinopenia, isosthenuria, and high serum alkaline phosphatase and alanine aminotransferase activities) also occurred in the prednisone-treated dogs. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that anti-inflammatory doses of orally administered glucocorticoids have the potential to adversely impact cardiac function in dogs by causing an increase in blood pressure and thus increased cardiac afterload.