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Background: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin‐angiotensin‐aldosterone system (RAAS) in cats is incompletely characterized. Hypothesis/Objectives: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. Animals: Twenty healthy client‐owned cats. Methods: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4‐week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time‐weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank‐sum testing. Results: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%‐86%; P =.009), angiotensin I (59% increase; IQR 27‐101%; P =.006), angiotensin II (56% increase; IQR 5‐70%; P =.023), angiotensin IV (42% increase; −19% to 89%; P =.013); and angiotensin 1‐7 (38% increase; IQR 9‐118%; P =.015). Conclusions and Clinical Importance: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Estrogen modulates the renin‐angiotensin‐aldosterone system (RAAS) in women, but sex differences have not been fully explored in dogs. Objective: We hypothesized that the RAAS profile of intact female (IF) Doberman Pinschers (DP) would differ from spayed female (SF) and intact male (IM) DP. Animals: Eighteen healthy DP (6 IF, 6 SF, 6 IM). Methods: Absolute and indexed RAAS metabolites, angiotensin‐converting enzyme (ACE) and ACE2 activities, and genotypes (pyruvate kinase dehydrogenase 4, titin, and ACE variants) were compared among sex groups using Kruskal‐Wallis or chi‐square tests, and linear regression controlling for age. Data are expressed as median (minimum, maximum) and P <.05 was considered significant. Results: The ACE activity was higher in IF DP (656 pmol/L; 436, 784) compared to SF DP (411 pmol/L; 287, 451; P =.01) and IM DP (365 pmol/L; 276, 1200; P =.04) after controlling for age. Angiotensin II, angiotensin I, and plasma renin activity marker (PRA‐S) were higher in IF DP compared to SF DP, but not significantly (P ≤.25). After controlling for age, angiotensin 1‐7/angiotensin I was lower in IF DP compared to SF DP (P =.01). Genotypes did not differ among groups. Most DP (94%) were ACE variant positive. Conclusions and Clinical Significance: Sex and reproductive status influenced the RAAS of DP, with IF DP showing genotype‐independent higher ACE activity. These findings hold implications for sterilization practices in female dogs, and support sex and reproductive status as a source of variability in RAAS studies. Additionally, the frequency of the ACE gene variant was very high in this group of DP. [ABSTRACT FROM AUTHOR]

Background: The influence of aldosterone breakthrough (ABT) on proteinuria reduction during renin‐angiotensin system (RAS) inhibition for spontaneous proteinuric chronic kidney disease (CKDP) has not been determined in dogs. Objectives: Determine whether ABT occurs in dogs with CKDP and if it is associated with decreased efficacy in proteinuria reduction during RAS inhibitor treatment. Animals: Fifty‐six client‐owned dogs with CKDP and 31 healthy client‐owned dogs. Methods: Prospective, multicenter, open‐label clinical trial. Dogs were treated with an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker alone or in combination at the attending clinician's discretion and evaluated at 5 time points over 6 months. Healthy dogs were used to determine the urine aldosterone‐to‐creatinine ratio cutoff that defined ABT. The relationship of ABT (present at ≥50% of visits) and proteinuria outcome (≥50% reduction in urine protein‐to‐creatinine ratio from baseline at ≥50% of subsequent visits) was evaluated. Mixed effects logistic regression was used to evaluate the relationship between clinical variables and outcomes (either successful proteinuria reduction or ABT). Results: Thirty‐six percent (20/56) of dogs had successful proteinuria reduction. Between 34% and 59% of dogs had ABT, depending on the definition used. Aldosterone breakthrough was not associated with proteinuria outcome. Longer duration in the study was associated with greater likelihood of successful proteinuria reduction (P =.002; odds ratio, 1.6; 95% confidence interval [CI], 1.2‐2.2). Conclusions and Clinical Importance: Aldosterone breakthrough was common in dogs receiving RAS inhibitors for CKDp but was not associated with proteinuria outcome. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) leads to low serum concentrations of vitamin D metabolites. Thus, hypovitaminosis D associated with CKD might contribute to disease progression via increased concentration of renin angiotensin aldosterone system (RAAS) mediators. Objectives: To evaluate whether supplementation with calcifediol affects equilibrium concentrations of selected mediators of the RAAS. We hypothesized that vitamin D supplementation will decrease concentration of circulating RAAS mediators in dogs with CKD. Animals: Six client‐owned adult dogs with IRIS Stage 2 and 3 CKD. Methods: Prospective study. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), RAAS mediators (angiotensin I/II/III/IV/1‐5/1‐7, and aldosterone), and surrogate angiotensin converting enzyme (ACE) activity (calculated by the ratio of angiotensin II to angiotensin I) were evaluated at baseline, after 3 months of calcifediol supplementation, and 2 months after discontinuing administration of supplement. Results: All serum vitamin D metabolite concentrations increased significantly by month 3 (P <.001): 25(OH)D (median 250 ng/mL; range, 204‐310), compared to baseline (median 43.2 ng/mL; range, 33.8‐58.3 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 57.3‐88.1 pg/mL) compared to baseline (median 35.2 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 68.4 ng/mL; range, 22.1‐142.0 ng/mL) compared to baseline (median 14.4 ng/mL; range, 9.0‐21.3 ng/mL). Calculated ACE activity was significantly lower at month 3 (median 0.5; range, 0.4‐1.0) compared to baseline (median 0.7; range, 0.6‐1.3; P =.01). There were no significant differences in any of the evaluated RAAS variables at any other time‐point. Conclusions and Clinical Importance: Short‐term calcifediol supplementation in this small group of CKD dogs appeared to decrease ACE activity. [ABSTRACT FROM AUTHOR]

Background: In people and dogs, torasemide has higher bioavailability, longer half‐life, and longer duration of action than equivalent doses of furosemide but data regarding pharmacological properties of torasemide in cats are limited. Objective: To assess pharmacokinetic and pharmacodynamic parameters of torasemide in healthy cats, and to investigate the effects of a single administration of torasemide on indicators of diuresis, plasma creatinine concentration, blood pressure, electrolyte concentrations and markers of the renin‐angiotensin‐aldosterone system (RAAS). Animals: Six clinically healthy adult European shorthair cats. Methods: Randomized 4‐period crossover design with 3 groups and 4 treatments. Pharmacokinetic parameters were obtained using a noncompartmental analysis, and the clinically effective dose was assessed using a Hill model. Results: Mean absolute bioavailability was estimated at 88.1%. Mean total body clearance was 3.64 mL/h/kg and mean terminal half‐life was 12.9 hours. Urine output significantly increased after torasemide administration (P <.001). The urine sodium : potassium ratio (uNa : uK) paralleled and was statistically correlated to urine output (P <.001). Administration of a single torasemide dose led to a significant dose‐dependent increase in urine aldosterone : creatinine ratio (uAldo : C; P <.001) and a transient decrease in plasma potassium concentration (P <.001) but did not affect blood pressure or plasma creatinine concentration. Conclusions and Clinical Importance: A single torasemide dose leads to a significant increase in diuresis and renin‐angiotensin‐aldosterone system (RAAS) activation in healthy cats, with high absolute bioavailability, and without clinically relevant adverse effects. Pharmacokinetic parameters indicate that once daily dosing of 0.27 mg/kg may be appropriate in a clinical setting. [ABSTRACT FROM AUTHOR]

Background: Activity of the circulating renin‐angiotensin‐aldosterone system (RAAS) has not been comprehensively characterized in cats with systemic hypertension (SH) or cardiomyopathy (CM), and the effects of furosemide or amlodipine treatment on the RAAS have not been fully evaluated in cats. Hypothesis/Objectives: To document RAAS activity in cats with SH or CM compared to healthy cats and determine how RAAS profiles change with furosemide or amlodipine treatment. Animals: Sixty‐six client‐owned cats: 15 with SH (7 amlodipine‐treated, 8 untreated), 17 with advanced CM (7 furosemide‐treated, 10 not furosemide‐treated), and 34 healthy cats. Methods: Equilibrium concentrations of RAAS peptides and aldosterone were quantified in serum samples by liquid chromatography‐mass spectrometry. Variables were compared between groups using Kruskal‐Wallis analysis with post hoc Holms‐corrected Dunn's testing. Results: Compared with healthy cats, cats with CM had higher concentrations of angiotensin I, aldosterone, and plasma renin activity (all P <.01), and these differences remained significant (P <.03) after considering subgroups of untreated or furosemide‐treated cats. Compared with healthy cats, untreated cats with SH showed no differences in RAAS biomarkers, whereas amlodipine‐treated cats had higher concentrations of angiotensins I, II, III, IV, and 1‐7, aldosterone, and plasma renin activity (all P <.03). Multivariable analysis determined that furosemide and amlodipine treatments were independent predictors of increased RAAS biomarker concentrations. Conclusions and Clinical Importance: Cats with CM had increased RAAS activity, whereas cats with untreated SH did not. Furosemide and amlodipine both led to nonspecific activation of both classical and alternative RAAS pathways in cats. [ABSTRACT FROM AUTHOR]

Background: The role of the renin‐angiotensin‐aldosterone system in cats with chronic kidney disease (CKD) is incompletely understood. Objective: To characterize components of the intrarenal renin‐angiotensin system (RAS) in cats with CKD. Animals: Eleven cats with naturally occurring CKD (CKD group) and 8 healthy control cats. Methods: Renal tissue samples were evaluated by reverse‐transcription polymerase chain reaction for renin, angiotensinogen, angiotensin‐converting enzyme (ACE), and angiotensin II type 1 receptor transcript levels, and by liquid chromatography‐mass spectrometry for quantification of angiotensin I, II, III, and IV concentrations. Linear mixed models were used to compare gene transcript levels and concentrations of angiotensin peptides between groups. Results: Cats of the CKD group were significantly older (P <.001) and more likely to be neutered (P =.007) than healthy control cats. Kidneys from cats with CKD had significantly higher transcript levels of angiotensinogen (P <.001) and lower transcript levels of ACE (P <.001) than those from control cats. Renal angiotensin I concentrations were increased in CKD compared with control kidneys (P =.001). No other significant differences in renal transcript levels or angiotensin peptide concentrations were noted between groups. Conclusion and Clinical Importance: The intrarenal RAS might be activated in cats with CKD. Small sample size and differences in age, neuter status, and dietary sodium intake between groups might have limited the ability to identify a significant difference in concentration of renal angiotensin II. [ABSTRACT FROM AUTHOR]

Background: Information regarding changes in renin‐angiotensin‐aldosterone system (RAAS) during cardiac remodeling after mitral valvuloplasty (MVP) in dogs remains lacking. Hypothesis/Objectives: To assess the longitudinal effects of MVP on circulating RAAS activity. Animals: Eight client‐owned dogs receiving MVP for myxomatous mitral valve disease (MMVD). Methods: This is a cohort study. Plasma renin activity (PRA), angiotensin II (AT2), aldosterone (PAC), blood urea nitrogen (BUN), and creatinine concentrations, were measured in these dogs before (baseline) and at 3 consecutive monthly follow‐ups (Post‐1M, Post‐2M, Post‐3M). Echocardiography was concomitantly used to assess the process of cardiac recovery after MVP. Results: The echocardiography revealed a significant decrease in LVIDDN, LA/Ao, FS, E velocity, E/A, E′ sep, S′ lat, E′ lat, and A′ lat after MVP compared with baseline (P <.05). There was a significant reduction in the PRA (2.45, 3.05, 2.74 vs 8.8 ng/mL/h; P =.002), AT2 (466, 315, 235 vs 1200 pg/mL; P =.009), and PAC (39.88, 47, 54.62 vs 179.5 pg/mL; P =.01), respectively at Post‐1M, Post‐2M, Post‐3M compared to the baseline. Additionally, BUN and creatinine concentrations decreased from Post‐1M. The RAAS variables showed significant, weak to moderate, relationship with selected echocardiographic variables. Conclusions and Clinical Importance: Mitral valvuloplasty contributes to decreased RAAS activity in MMVD dogs, which paralleled the process of cardiac reverse remodeling up to Post‐3M. This information facilitates formulating strategies to optimize clinical outcomes for dogs after MVP. [ABSTRACT FROM AUTHOR]

A 14‐year‐old male castrated domestic medium‐hair cat with diabetes mellitus was evaluated for vomiting, diarrhea, and anorexia. Two weeks before presentation, the cat had been diagnosed with congestive heart failure and started on furosemide. Initial diagnostic testing identified hypokalemia, systemic hypertension, and hypertrophic cardiomyopathy phenotype, and plasma aldosterone concentration was moderately increased. Abdominal ultrasound examination disclosed bilateral adrenomegaly and a right renal mass, and cytology of a needle aspirate of the mass was consistent with malignant neoplasia. The cat was treated with amlodipine and spironolactone. Because of the unusual presentation for hyperaldosteronism, a comprehensive profile of renin‐angiotensin‐aldosterone system (RAAS) peptides was performed. Results from multiple timepoints indicated persistently and markedly increased plasma renin activity and generalized RAAS upregulation. In addition to the lack of adrenal tumor, the markedly increased plasma renin activity was atypical for primary hyperaldosteronism. These clinical findings are suggestive of primary hyperreninism, a condition previously unreported in cats. The concurrent presence of a renal neoplasm suggests the possibility of a renin‐secreting tumor. [ABSTRACT FROM AUTHOR]

Background: The renin‐angiotensin‐aldosterone system (RAAS), when chronically activated, is harmful and RAAS‐suppressive drugs are beneficial in the treatment of congestive heart failure (CHF). Mineralocorticoid receptor antagonists are widely used in the treatment of CHF in people. Hypothesis/Objectives: To determine if a mineralocorticoid receptor antagonist (spironolactone) is beneficial and safe in CHF due to myxomatous mitral valve disease (MMVD) of varying severity, we hypothesized that, when combined with furosemide, a combination product (S+BNZ) containing the ACE inhibitor (ACE‐I), benazepril, and spironolactone, would be superior to benazepril alone. Animals: Five hundred and sixty‐nine client‐owned dogs, with MMVD and CHF (ACVIM Stage C) of ≤10‐days' duration. Methods: After initial stabilization, dogs were randomized into a positive‐controlled, double‐blind, multicenter trial, to receive furosemide plus S+BNZ or furosemide plus benazepril. The primary outcome variable was the percentage of dogs reaching cardiac endpoint before Day 360. Cardiac endpoint was defined as cardiac death or euthanasia, recurrence of pulmonary edema, necessity for nonauthorized cardiac drug(s) or a furosemide dosage >8 mg/kg/d. Results: A significantly lower percentage of dogs treated with S+BNZ reached the primary outcome variable by Day 360 (OR = 0.56; 95% CI, 0.32‐0.98; P =.04) and risk of dying or worsening from cardiac causes, was significantly reduced (HR = 0.73; 95% CI = 0.59‐0.89, P =.002) vs benazepril alone. Adverse events, potentially associated with treatment, were rare and equal between groups. Conclusion and Clinical Importance: The combination of S+BNZ is effective, safe, and superior to benazepril alone, when used with furosemide for the management of mild, moderate or severe CHF caused by MMVD in dogs. [ABSTRACT FROM AUTHOR]

Background: Use of telmisartan for the treatment of proteinuria in dogs has not been thoroughly investigated. Hypothesis/Objectives: Telmisartan can be effective for the treatment of proteinuria in dogs. Animals: Forty‐four client‐owned dogs with proteinuria. Methods: Retrospective study. Dogs diagnosed with clinically relevant proteinuria (nonazotemic dogs with a urine protein‐to‐creatinine ratio [UPC] ≥2 and azotemic dogs with UPC ≥0.5) were separated into 3 groups: telmisartan alone, with benazepril, or with mycophenolate. The UPC was recorded before treatment and at subsequent follow‐ups (1, 3, 6, and 12 months, as available). Response to treatment was categorized as complete (UPC ˂0.5), partial (UPC decreased by ≥50% but still ≥0.5), or no response (UPC decreased by <50%). Serum creatinine and potassium concentrations and arterial pressure also were recorded. Results: In the telmisartan group, treatment response (UPC ˂0.5 or decreased by ≥50%) was observed in 70%, 68%, 80%, and 60% of dogs at 1, 3, 6, and 12 months follow‐up, respectively. No significant changes were noted in serum creatinine or potassium concentrations, or in arterial blood pressure at all follow‐up times. Adverse effects consisted of mild self‐limiting gastrointestinal signs in 5 dogs. Two dogs developed clinically relevant azotemia that required discontinuation of the treatment before the first follow‐up. Conclusions and Clinical Importance: Telmisartan can be considered for treatment of proteinuria in dogs, alone or in combination with other treatments for proteinuria. [ABSTRACT FROM AUTHOR]

Background: Diuretic braking during furosemide continuous rate infusion (FCRI) curtails urine production. Hypothesis: Renin‐angiotensin‐aldosterone system (RAAS) activation mediates braking, and RAAS inhibition will increase urine production. Animals Ten healthy purpose‐bred male dogs. Methods: Dogs received placebo, benazepril, or benazepril and spironolactone PO for 3 days before a 5‐hour FCRI (0.66 mg/kg/h) in a 3‐way, randomized, blinded, cross‐over design. Body weight (BW), serum creatinine concentration (sCr), serum electrolyte concentrations, PCV, and total protein concentration were measured before PO medications, at hours 0 and 5 of FCRI, and at hour 24. During the FCRI, water intake, urine output, urine creatinine concentration, and urine electrolyte concentrations were measured hourly. Selected RAAS components were measured before and after FCRI. Variables were compared among time points and treatments. Results: Diuretic braking and urine production were not different among treatments. Loss of BW, hemoconcentration, and decreased serum chloride concentration occurred during FCRI with incomplete recovery at hour 24 for all treatments. Although unchanged during FCRI, sCr increased and serum sodium concentration decreased at hour 24 for all treatments. Plasma aldosterone and angiotensin‐II concentrations increased significantly at hour 5 for all treatments, despite suppressed angiotensin‐converting enzyme activity during benazepril background treatment. Conclusions: The neurohormonal profile during FCRI supports RAAS mediation of diuretic braking in this model. Background treatment with benazepril with or without spironolactone did not mitigate braking, but was well tolerated. Delayed changes in sCr and serum sodium concentration and incomplete recovery of hydration indicators caused by furosemide hold implications for clinical patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Refractory congestive heart failure (CHF) and associated diuretic resistance are not well defined. Objectives: To characterize renal function, electrolyte concentrations, indices of diuretic efficacy, and renin‐angiotensin‐aldosterone system (RAAS) activation in dogs with naturally occurring heart disease (HD) in American College of Veterinary Internal Medicine stages B1, B2, C, and D and to determine their usefulness in defining HD stages. Animals: Group 1:149 dogs with HD stages B1, B2, C, and D. Group 2:22 dogs with HD stages C and D. Methods: Group 1: Renal parameters, serum and urine electrolyte and diuretic concentrations, and urine aldosterone concentrations were measured. Medication dosages and measured variables were compared among stages. Correlation of furosemide dosages to serum concentrations was explored. Group 2: Angiotensin‐converting enzyme activity and RAAS components were measured and compared among CHF stages. Results: Serum chloride concentration was the best differentiator of HD stage. Furosemide PO dosages (≤6 mg/kg/day) were weakly correlated with serum furosemide concentrations, whereas higher dosages were not significantly correlated. Angiotensin‐converting enzyme inhibitor dosage and RAAS inhibition were greater in stage D, compared to stage C dogs. Conclusions and Clinical Importance: Hypochloremia is a useful marker for stage D HD in dogs. Poor furosemide dosage correlation to serum concentration may indicate variable and poor absorption, especially at higher dosages, advanced disease, or both. A small number of stage D dogs met proposed criteria for diuretic resistance. Greater RAAS inhibition in stage D versus stage C indicates effectiveness of RAAS‐suppressive treatments in this group of dogs with refractory CHF. [ABSTRACT FROM AUTHOR]

Background: The renin‐angiotensin‐aldosterone system (RAAS) is activated in humans with portal hypertension (PH) associated with liver disease. However, involvement of RAAS in dogs with intrahepatic PH is not clear. Objective: To measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in dogs with PH (chronic hepatitis [CH] and primary hypoplasia of the portal vein [PHPV]), dogs with extrahepatic congenital portosystemic shunt (EH‐CPSS), and healthy dogs and to determine whether the RAAS is activated in dogs with PH. Animals: Twenty‐seven dogs with acquired portosystemic collaterals (APSCs; 15 dogs with CH, 12 dogs with PHPV), 9 dogs with EH‐CPSS, and 10 healthy dogs. Methods: Retrospective study. Plasma renin activity and PAC were measured by radioimmunoassay. Results: Plasma renin activity was significantly higher in the CH group (median, 4.4 ng/mL/h) than in the EH‐CPSS (median, 1.0 ng/mL/h; P <.01) and the healthy (median, 1.1 ng/mL/h; P <.01) groups. No significant differences were found between the PHPV group (median, 2.2 ng/mL/h) and other groups. Plasma aldosterone concentration was significantly higher in the CH (median, 111.0 pg/mL) and PHPV (median, 89.5 pg/mL) groups than in the EH‐CPSS (median, 1.0 pg/mL; P <.001, P <.01, respectively) and healthy (median, 14.5 pg/mL; P <.001, P <.05, respectively) groups. Conclusions and Clinical Importance: Activation of the RAAS contributes to the pathophysiology of intrahepatic PH in dogs, suggesting that spironolactone may not only be effective for the treatment of ascites but also for the suppression of intrahepatic PH. [ABSTRACT FROM AUTHOR]

Background: The effects of sacubitril/valsartan (S/V) on the renin‐angiotensin‐aldosterone system (RAAS) in dogs with cardiomegaly secondary to myxomatous mitral valve disease (MMVD) are currently unknown. Objectives: To determine the pharmacodynamic effects of S/V on the RAAS, natriuretic peptide concentrations, systolic arterial pressure (SAP), tests of renal function, and serum electrolyte concentrations in dogs with cardiomegaly secondary to MMVD. Animals: Thirteen client‐owned dogs weighing 4‐15 kg with American College of Veterinary Internal Medicine (ACVIM) Stage B2 MMVD. Methods: Prospective, randomized, double‐blind, placebo‐controlled pilot study of S/V in dogs with ACVIM Stage B2 MMVD. Results: Thirteen dogs were recruited: S/V (n = 7) and placebo (n = 6). The median percentage increase in urinary aldosterone to creatinine ratio (UAldo : C) between day 0 and day 30 was significantly lower in the S/V group (12%; P = .032) as compared with the placebo group (195%). The median percentage decrease of NT‐proBNP concentration from day 0 to day 30 was not statistically different between groups (P = .68). No statistical differences were seen in echocardiographic, thoracic radiographic, SAP, or serum biochemical test results measured at any time point between groups. No adverse events were observed for dogs in either group. Conclusion and Clinical Importance: Sacubitril/valsartan may provide a new pharmaceutical method to effectively inhibit the RAAS in dogs with ACVIM Stage B2 MMVD. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, electrolyte homeostasis, and renal function. Blood pressure, serum sodium concentrations, and urinary albumin excretion are higher in Greyhounds than other purebred and mixed-breed dogs. Hypothesis: Alterations in the RAAS in Greyhounds are associated with hemodynamic and clinicopathologic differences observed in the breed. Animals: Clinically healthy Greyhound and non-Greyhound dogs consecutively enrolled as blood donors (n = 20/group). Methods: Prospective study. Standard chemical analysis was performed on serum and urine. Serum angiotensin-converting enzyme (ACE) activity was determined by fluorometric assay. All other RAAS hormones were determined by radioimmunoassay. Symmetric dimethylarginine (SDMA) was measured by immunoassay. Measurements were compared to blood pressure and urine albumin concentration. Data are presented as mean ± SD or median, range. Results: Serum creatinine (1.5 ± 0.2 vs 1.0 ± 0.1 mg/dL, P < .001), sodium (149, 147–152 vs 148, 146–150 mEq/L, P = .017), and SDMA (16.1 ± 2.9 vs 12.2 ± 1.8 μg/dL, P < .001) were significantly higher in Greyhounds versus non-Greyhounds, respectively. Plasma renin activity (0.69, 0.10–1.93 vs 0.65, 0.27–2.93 ng/mL/h, P = .60) and ACE activity (4.5, 2.1–8.5 vs 4.6, 2.1–11.4 activity/mL; P = .77) were similar between groups and did not correlate with higher systolic pressures and albuminuria in Greyhounds. Plasma aldosterone concentration was significantly lower in Greyhounds versus non-Greyhounds (11, 11–52 vs 15, 11–56 pg/mL, respectively, P = .002). Conclusions and clinical importance: Basal RAAS activation did not differ between healthy Greyhounds and non-Greyhounds. Lower aldosterone concentration in Greyhounds is an appropriate physiologic response to higher serum sodium concentration and blood pressure, suggesting that angiotensin II effects in the renal tubule predominate over those of aldosterone. [ABSTRACT FROM AUTHOR]

Background Role of renin-angiotensin aldosterone system ( RAAS) in feline systemic hypertension is poorly understood. Objectives Examine plasma renin activity ( PRA) and plasma aldosterone concentrations ( PAC) in normotensive and hypertensive cats with variable renal function and in response to antihypertensive therapy. Animals One hundred and ninety-six cats >9 years from first opinion practice. Methods PRA, PAC, and aldosterone-to-renin ratio ( ARR) were evaluated in cats recruited prospectively and grouped according to systolic blood pressure ( SBP) and renal function (nonazotemic normotensive [Non-Azo- NT], nonazotemic hypertensive [Non-Azo- HT], azotemic normotensive [Azo- NT], azotemic hypertensive [Azo- HT]). Changes in PRA and PAC were evaluated with antihypertensive therapy (amlodipine besylate). Results Plasma renin activity (ng/mL/h; P = .0013), PAC (pg/mL; P < .001), and ARR ( P = 0.0062) differed significantly among groups. PRA (ng/mL/h) was significantly lower in hypertensive (Non-Azo- HT; n = 25, median 0.22 [25th percentile 0.09, 75th percentile 0.39], Azo- HT; n = 44, 0.33 [0.15, 0.48]) compared with Non-Azo- NT cats (n = 57, 0.52 [0.28, 1.02]). Azo- HT cats had significantly higher PAC (n = 22, 149.8 [103.1, 228.7]) than normotensive cats (Non-Azo- NT; n = 26, 45.4 [19.6, 65.0], Azo- NT; n = 18, 84.1 [38.6, 137.8]). ARR was significantly higher in Azo- HT (n = 20, 503.8 [298.8, 1511]) than Azo- NT cats (n = 16, 97.8 [77.0, 496.4]). Significant increase in PRA was documented with antihypertensive therapy (pretreatment [n = 20] 0.32 [0.15-0.46], posttreatment 0.54 [0.28, 1.51]), but PAC did not change. Conclusions and Clinical Importance Hypertensive cats demonstrate significantly increased PAC with decreased PRA. PRA significantly increases with antihypertensive therapy. Additional work is required to determine the role of plasma aldosterone concentration in the pathogenesis of hypertension and whether this relates to autonomous production or activation of RAAS without demonstrable increase in PRA. [ABSTRACT FROM AUTHOR]

Standard therapy forms the basic foundation for care of dogs with glomerular disease, as it is herein recommended for use in all affected animals regardless of causation of the disease. Consensus recommendations target the evaluation and management of proteinuria, inhibition of the renin-angiotensin-aldosterone system, modification in dietary intake with special consideration for those nutrients with renal effects, diagnosis and treatment of systemic hypertension, and evaluation and management of body fluid volume status in dogs with glomerular disease. [ABSTRACT FROM AUTHOR]

Background Hypertension is present in some hyperthyroid cats at diagnosis or can develop after treatment for hyperthyroidism. Activation of the renin-angiotensin-aldosterone system ( RAAS) could be involved in the pathogenesis of hypertension. Hypothesis Hyperthyroid cats that develop hypertension before or after treatment for hyperthyroidism will have greater RAAS activation than normotensive cats. Animals Ninety-nine hyperthyroid cats. Methods Retrospective case-control study. Plasma renin activity ( PRA) and plasma aldosterone concentration ( PAC) were measured in untreated hyperthyroid hypertensive cats ( HT-Pre group), initially normotensive hyperthyroid cats that develop hypertension after treatment ( HT-Post group), and hyperthyroid cats that are normotensive ( NT group). Data are presented as median [25th, 75th percentile]. Results Baseline PRA was not significantly different among the 3 groups ( HT-Pre group 1.50 [0.05, 2.37] ng/mL/h, HT-Post group 0.66 [0.17, 2.31] ng/mL/h, NT group 1.11 [0.57, 2.18] ng/mL/h; P = .44). PRA decreased significantly after treatment in the NT group (1.09 [0.53, 2.47] versus 0.22 [0.05, 0.76] ng/mL/h; P < .001) and the HT-Post group (0.71 [0.17, 2.33] versus 0.28 [0.07, 0.57] ng/mL/h; P = .006). Baseline PAC was not significantly different among the 3 groups ( HT-Pre group 72.2 [40.0, 145.6] pg/mL, HT-Post group 69.7 [43.3, 142.6] pg/mL, NT group 109.0 [68.2, 184.6] pg/mL; P = .10). PAC decreased significantly after treatment in the NT group (114.4 [56.6, 204.1] versus 59.5 [32.4, 98.2] pg/mL; P < .001) but did not change significantly in the HT-Post group (61.2 [44.9, 124.0] versus 58.4 [42.0, 97.7] pg/mL; P = .59). Conclusions and Clinical Importance RAAS activation occurs in hyperthyroid cats, but is not associated with the development of hypertension. PAC is not influenced by changes in PRA in hyperthyroid cats that develop hypertension after treatment, perhaps indicating RAAS dysfunction in these cats. [ABSTRACT FROM AUTHOR]

Background The renin-angiotensin-aldosterone system ( RAAS) and hypothalamic-pituitary-adrenal axis ( HPAA) and their interactions during illness and hypoperfusion are important to maintain organ function. HPAA dysfunction and relative adrenal insufficiency ( RAI) are common in septic foals. Information is lacking on the RAAS and mineralocorticoid response in the context of RAI in newborn sick foals. Objectives/Hypothesis To investigate the RAAS, as well as HPAA factors that interact with the RAAS, in hospitalized foals, and to determine their association with clinical findings. We hypothesized that critical illness in newborn foals results in RAAS activation, and that inappropriately low aldosterone concentrations are part of the RAI syndrome of critically ill foals. Animals A total of 167 foals ≤3 days of age: 133 hospitalized (74 septic, 59 sick nonseptic) and 34 healthy foals. Methods Prospective, multicenter, cross-sectional study. Blood samples were collected on admission. Plasma renin activity ( PRA) and angiotensin- II ( ANG- II), aldosterone, ACTH, and cortisol concentrations were measured in all foals. Results ANG- II, aldosterone, ACTH, and cortisol concentrations as well as ACTH/aldosterone and ACTH/cortisol ratios were higher in septic foals compared with healthy foals ( P < .05). No difference in PRA between groups was found. High serum potassium and low serum chloride concentrations were associated with hyperaldosteronemia in septic foals. Conclusions and Clinical Importance RAAS activation in critically ill foals is characterized by increased ANG- II and aldosterone concentrations. Inappropriately low cortisol and aldosterone concentrations defined as high ACTH/cortisol and ACTH/aldosterone ratios in septic foals suggest that RAI is not restricted to the zona fasciculata in critically ill newborn foals. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin-aldosterone system (RAAS) is activated in states of decreased cardiac output and by certain cardiovascular therapeutic agents, such as loop diuretics and vasodilators. Hypothesis: Short-term treatment with the inodilator, pimobendan, will not activate the circulating RAAS because its vasodilatory action will be offset by its positive inotropic property, thereby ameliorating RAAS stimulation at the juxtaglomerular apparatus. Furthermore, pimobendan will suppress RAAS activation produced by furosemide. Animals: Nine healthy laboratory dogs were used in this study. Methods: Experimental, cross-over study. Dogs were administered pimobendan (0.5 mg/kg q12h) for 4 days followed by furosemide (2 mg/kg q12h) and then, after a wash-out period, a combination of the drugs. Aldosterone : creatinine (A : Cr) was measured at the end of each treatment cycle. Results: There was no significant increase in the average urinary A : Cr with the administration of pimobendan (control urinary A : Cr = 0.46, standard deviation (SD) 0.33; pimobendan A : Cr = 0.48, SD 0.28). There was a significant increase in the average urinary A : Cr after administration of furosemide (urinary A : Cr = 1.3, SD 0.70) and with the combination of furosemide and pimobendan (urinary A : Cr = 2.9, SD 1.6). Conclusions and Clinical Relevance: Short-term administration of high-dose pimobendan, does not activate the RAAS in healthy dogs. Pimobendan did not prevent RAAS activation associated with furosemide therapy. These results in healthy dogs suggest that furosemide therapy, with or without pimobendan, should be accompanied by RAAS suppressive therapy. [ABSTRACT FROM AUTHOR]

Erratum for The renin-angiotensin-aldosterone system and its suppression GLO:55QJ/01sep19:jvim15615-fig-0001.jpg PHOTO (COLOR): The renin-angiotensin-aldosterone system peptide cascade (RAAS Fingerprint) is illustrated as a pedigree starting at Angiotensin 1. The novel peptides angiotensin (1,12) and angiotensin (1,25) may be directly derived from angiotensinogen and serve as precursors for angiotensin peptides such as AngII. [Extracted from the article]