Dose–response of benazepril on biomarkers of the classical and alternative pathways of the renin–angiotensin–aldosterone system in dogs

Figures

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  Figure 1. Simplified schematic representation of the classical (red shading) and alternative (green shading) arms of the renin–angiotensin–aldosterone system. Red shading indicates activity of the classical renin–angiotensin–aldosterone system (RAAS); green shading indicates activity of the alternative RAAS. The sizes of the circles are proportional to the expected concentration of each angiotensin peptide in a healthy dog. Arrows indicate enzymes catalyzing conversion of metabolites. ACE angiotension converting enzyme, ACE2 angiotension converting enzyme 2, Aldo aldosterone, Ang angiotensin, AP aminopeptidases, NEP neutral endopeptidase.

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  Figure 2. Schematic representation of crossover study design and timeline for sample collection. There are three experimental cycles (treatment periods) during which randomized groups of 3 dogs cross over to receive each of 3 benazepril doses (0.125 mg/kg twice daily, 0.25 mg/kg twice daily, and 0.5 mg/kg once daily). Prior to each cycle, there is a 5-day period of RAAS activation (by consuming a low-sodium diet); between cycles, there is a 10-day washout period during which dogs consume their normal diet. Diagnostic testing performed at each timepoint is indicated by color-coded shaded circles. See text for further details. D, day of the study period; q12h, twice daily; q24h, once daily.

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  Figure 3. Twelve hour time-weighted average of RAAS biomarkers in nine healthy beagle dogs treated with a single dose of benazepril at 0.125, 0.25, or 0.5 mg/kg orally. Units for time-weighted averages of biomarkers are pmol/L; ratios are unitless. The horizontal line represents median, box represents quartiles, and whiskers represent range, with outliers plotted as dots. Outliers are defined as point occurring > 1.5 × IQR higher than Q3 or lower than Q1. Ang angiotensin, PRA-S surrogate measure of plasma renin activity, ACE-S surrogate measure of angiotensin-converting enzyme activity, ALT-S surrogate measure of alternative RAAS pathway activity, AA2 ratio measure of adrenal responsiveness to angiotensin II.

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  Figure 4. Comparison of treatment effect size (percent difference in 12-h time-weighted averages) on RAAS biomarkers in nine healthy beagle dogs treated with a single oral dose of benazepril at 0.125, 0.25, or 0.5 mg/kg. The extent of treatment effect for each dosage comparison is calculated as (time-weighted average for dosage B – time-weighted average for dosage A)/(time-weighted average for dosage B). Positive bars indicate higher values of the indicated biomarker for the higher benazepril dosage (corresponding to positive values for the extent of treatment effect in Table 4). In comparison, negative bars indicate lower values of the indicated biomarker with the higher benazepril dosage (corresponding to negative values for the extent of treatment effect in Table 4). Error bars represent the standard error of treatment effect size. Red shading indicates activity of the classical RAAS; green shading indicates activity of the alternative RAAS; grey shading with diagonal lines indicates other ratios. Ang angiotensin, PRA-S surrogate measure of plasma renin activity, ACE-S surrogate measure of angiotensin-converting enzyme activity, ALT-S surrogate measure of alternative RAAS pathway…