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Introduction
Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation.Animals, Materials and Methods
This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum K+ concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone.Results
The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C.Discussion
Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens.Conclusions
Approximately 30% of dogs being treated for heart disease and CHF satisfied the definition of ABT. Identifying patient subpopulations experiencing ABT may help guide future study design and clinical decision-making. 相似文献3.
Sarah Spencer Caroline Wheeler-Jones Jonathan Elliott 《Journal of veterinary pharmacology and therapeutics》2020,43(3):243-267
There is a growing body of experimental and clinical evidence supporting mineralocorticoid receptor (MR) activation as a powerful mediator of renal damage in laboratory animals and humans. Multiple pathophysiological mechanisms are proposed, with the strongest evidence supporting aldosterone-induced vasculopathy, exacerbation of oxidative stress and inflammation, and increased growth factor signalling promoting fibroblast proliferation and deranged extracellular matrix homeostasis. Further involvement of the MR is supported by extensive animal model experiments where MR antagonists (such as spironolactone and eplerenone) abrogate renal injury, including ischaemia-induced damage. Additionally, clinical trials have shown MR antagonists to be beneficial in human chronic kidney disease (CKD) in terms of reducing proteinuria and cardiovascular events, though current studies have not evaluated primary end points which allow conclusions to made about whether MR antagonists reduce mortality or slow CKD progression. Although differences between human and feline CKD exist, feline CKD shares many characteristics with human disease including tubulointerstitial fibrosis. This review evaluates the evidence for the role of the MR in renal injury and summarizes the literature concerning aldosterone in feline CKD. MR antagonists may represent a promising therapeutic strategy in feline CKD. 相似文献
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Christina L. Marino;Jonathan D. Foster; 《Journal of veterinary internal medicine / American College of Veterinary Internal Medicine》2024,38(4):2344-2347
This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA. 相似文献
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J. N. King C. Christinaz G. Strehlau J. Hornfeld 《Journal of veterinary pharmacology and therapeutics》2018,41(3):485-489
To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin‐converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel‐group design study: A (control, placebo twice daily (BID)); B (0.5–1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25–0.5 mg/kg benazepril BID); D (0.25–0.5 mg/kg benazepril and 0.125–0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25–0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5–1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan. 相似文献
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K Kelers JL Devi GA Anderson P Zahra JH Vine T Whittem 《Australian veterinary journal》2013,91(8):312-319
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M.R. O'Grady M.L. O'Sullivan S.L. Minors R. Horne 《Journal of veterinary internal medicine / American College of Veterinary Internal Medicine》2009,23(5):977-983
Background: Angiotensin converting enzyme inhibitors (ACEIs) are recommended in people to treat asymptomatic (occult) dilated cardiomyopathy (DCM). Efficacy of therapy in occult DCM in dogs is unknown.
Hypothesis: ACEIs, specifically benazepril hydrochloride (BH), will delay the onset of overt DCM in Doberman Pinschers.
Animals: Ninety-one Doberman Pinschers were studied, 57 dogs received BH, and 34 dogs no ACEI.
Methods: Retrospective study of the medical records of all Doberman Pinschers with occult DCM that received BH or no ACEI between April 1989 and February 2003. Two criteria of left ventricular enlargement were used for enrollment: one independent of body weight (BW) (C1) and the other indexed to BW (C2). Cox proportional hazards analyses were used to identify variables associated with the onset of overt DCM.
Results: On univariate analysis the median time to onset of overt DCM was significantly longer for the benazepril group (for C1: 425 days for BH, 95% confidence interval [CI] 264–625 days; 339 days for no ACEI, CI 172–453 days, P = .02; for C2: 454 days for BH, CI 264–628 days; 356 days for no ACEI, CI 181–547 days, P = .02). The hazard ratio (HR) (benazepril/no ACEI) was 0.57, CI 0.35–0.94, P = .03 for C1; HR = 0.56, CI 0.34–0.93, P = .02 for C2. On multivariate analysis, BH significantly delayed onset of overt DCM (HR [benazepril/no ACEI] = 0.45, CI 0.26–0.78, P < .01, for C1; HR = 0.36, CI 0.21–0.63, P < .01, for C2).
Conclusions: BH in particular and ACEIs in general might delay the progression of occult DCM. Prospective studies are warranted to test this theory. 相似文献
Hypothesis: ACEIs, specifically benazepril hydrochloride (BH), will delay the onset of overt DCM in Doberman Pinschers.
Animals: Ninety-one Doberman Pinschers were studied, 57 dogs received BH, and 34 dogs no ACEI.
Methods: Retrospective study of the medical records of all Doberman Pinschers with occult DCM that received BH or no ACEI between April 1989 and February 2003. Two criteria of left ventricular enlargement were used for enrollment: one independent of body weight (BW) (C1) and the other indexed to BW (C2). Cox proportional hazards analyses were used to identify variables associated with the onset of overt DCM.
Results: On univariate analysis the median time to onset of overt DCM was significantly longer for the benazepril group (for C1: 425 days for BH, 95% confidence interval [CI] 264–625 days; 339 days for no ACEI, CI 172–453 days, P = .02; for C2: 454 days for BH, CI 264–628 days; 356 days for no ACEI, CI 181–547 days, P = .02). The hazard ratio (HR) (benazepril/no ACEI) was 0.57, CI 0.35–0.94, P = .03 for C1; HR = 0.56, CI 0.34–0.93, P = .02 for C2. On multivariate analysis, BH significantly delayed onset of overt DCM (HR [benazepril/no ACEI] = 0.45, CI 0.26–0.78, P < .01, for C1; HR = 0.36, CI 0.21–0.63, P < .01, for C2).
Conclusions: BH in particular and ACEIs in general might delay the progression of occult DCM. Prospective studies are warranted to test this theory. 相似文献
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探讨了肾素血管紧张素系统(renin angiotensin system,RAS)两条轴对大鼠非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)肝脏损伤的相互负向调节作用。30只雄性SD大鼠随机分为正常对照组、模型组和用药组。除正常对照组外,其余2组饲喂高脂饲料,用药组另外给伐他汀50 mg/kg·d。3周后,宰杀大鼠,测定血清中甘油三酯(TG)、谷丙转氨酶(ALT)、谷草转氨酶(AST)的含量;测定肝组织匀浆羟自由基(·OH)、一氧化氮合酶(NOS)、超氧化物歧化酶(SOD)、总抗氧化能力(T-AOC)酶活性;ELISA法测定组织匀浆中血管紧张素Ⅱ(AngⅡ)、血管紧张素1-7(Ang1-7)及白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)含量;Western blot分析肝组织血管紧张素转化酶(ACE)、血管紧张素转化酶2(ACE2)、血管紧张素Ⅱ受体1亚型(AT1R)、Mas受体(MasR)蛋白水平。结果:与正常对照组相比,模型组大鼠血清TG、AST和ALT含量以及·OH和NOS活性均显著升高(P<0.05), T-AOC、SOD活性显著降低(P<0.05);IL-1β和TNF-α含量极显著升高(P<0.01);ACE、ACE2的蛋白表达水平与ACE/ACE2的比值均显著升高(P<0.05),AngⅡ、Ang1-7含量与AT1R表达升高(P<0.05),MasR表达有升高趋势(P>0.05)。结论:高脂饲料连续饲喂3周可诱导大鼠发生NAFLD,肝脏局部RAS两条轴均处于激活状态,ACE介导AngⅡ-AT1R经典轴促进肝损伤,而ACE2介导Ang1-7-MasR轴抵抗肝损伤;ACE2负性调节RAS作用,对大鼠NAFLD时肝脏氧化应激及炎性损伤有一定保护作用。 相似文献
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Angiotensin I-converting enzyme (ACE) level measurement in blood samples is an important tool in human medicine for the detection, treatment and control of diseases such as sarcoidosis and hypertension. Recently ACE has been advocated as being correlated to athletic aptitude in human athletes and a genetic polymorphism has been shown to be responsible for the enzymatic levels in the circulation. The objective of this research was to evaluate the effects of acute exercise in horses in order to increase the understanding of a possible correlation between ACE levels in plasma and performance in equine athletes. A standardised exercise test (SET) to fatigue was conducted on 8 horses and repeated venous blood collections carried out for ACE activity measurements before, during and after the SET. Our results show an increase in ACE activity up to fatigue and a return to baseline values at 30 min post exercise. 相似文献
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Fu-Yuan CHENG Yu-Tse LIU Tien-Chun WAN Liang-Chuan LIN Ryoichi SAKATA 《Animal Science Journal》2008,79(1):122-128
In order to produce angiotensin I‐converting enzyme (ACE) inhibitor for application in functional food, chicken bones were gathered from a meat processing factory and then hydrolyzed with Alcalase, pepsin and trypsin for 12 h. The hydrolysates were lyophilized, stored at ?80°C and tested experimentally every 2 h for pH value, peptide content, degree of hydrolysis (DH), electrophoresis and activity of ACE inhibitor. The hydrolysates of Alcalase had the highest peptide content and DH. The components of more than 66 kDa had disappeared in hydrolysates of Alcalase and trypsin after 2 h of hydrolysis. The hydrolysates of Alcalase were more active in inhibiting ACE, especially when hydrolyzed at 4 and 8 h, and also had low IC50 values of 1.960 and 0.945 mg/mL. According to the results of DH and electrophoresis, the higher activity of ACE inhibitor is assumed to be derived from the low molecular peptides in hydrolysates of Alcalase. Chicken leg bone has a high potential to be utilized to develop ACE inhibitory peptides as a potential ingredient of functional food intended to alleviate hypertension. 相似文献
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Reasons for performing study: Studies in man have shown a correlation between Angiotensin I‐converting enzyme (ACE) genetic polymorphisms, ACE activity in the blood and superior athletic performance in sports requiring endurance. It has been hypothesised that the same correlation occurs in horses. There is no information in the literature concerning the effects of training on ACE activity in equine plasma. Hypothesis: Exercise training influences the activity of circulating ACE and the response observed is dependent on the exercise protocol. Methods: Thirteen horses of mixed breeds were randomly allocated 2 different training protocols to be carried out for a period of 15 weeks. Blood samples were collected from each horse before the beginning of training to determine baseline values. Subsequent sampling took place every 15 days throughout the training phase and for 8 weeks of paddock rest. Angiotensin I‐converting enzyme activity was determined by automated spectrophotometry. Results: Training for 15 weeks significantly increased plasma ACE activity, irrespective of training protocol. Differences observed in ACE activity pattern between the 2 training protocols were not statistically significant. Increase in ACE activity peaked with maximum workload. As soon as training was interrupted, ACE levels significantly decreased. Conclusions and discussion: Exercise training affects levels of ACE activity in equine plasma. The mechanism for this is not yet elucidated, but cardiovascular adaptation to exercise and blood pressure changes might be involved in this regulation. Potential relevance: Exercise training produced a gradual increase in enzymatic activity and might warrant the use of ACE as a tool for fitness monitoring. Angiotensin I‐converting enzyme enzymatic activity in the plasma might be directly correlated to a change in genetic expression and that variability must be taken into account when evaluating results from horses undergoing a physical training programme. 相似文献
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U. Sent R. Gössl J. Elliott H. M. Syme T. Zimmering 《Journal of veterinary internal medicine / American College of Veterinary Internal Medicine》2015,29(6):1479-1487
Background
The efficacy and benefits of telmisartan in cats with chronic kidney disease (CKD) have not previously been reported.Hypothesis
Long‐term treatment of cats with CKD using telmisartan decreases urine protein‐to‐creatinine ratio (UP/C) similar to benazepril.Animals
Two‐hundred and twenty‐four client‐owned adult cats with CKD.Methods
Prospective, multicenter, controlled, randomized, parallel group, blinded clinical trial with noninferiority design. Cats were allocated in a 1 : 1 ratio to either telmisartan (1 mg/kg; n = 112) or benazepril (0.5–1.0 mg/kg; n = 112) PO q24 h. The primary endpoint was prospectively defined as the change in proteinuria (benazepril:telmisartan) based on a log transformed weighted average of UP/C change from baseline (AUC 0→t/t) as a percentage compared using a confidence interval (CI) approach. Changes of UP/C from baseline were assessed on all study days and corrected for multiple comparisons.Results
Telmisartan proved noninferior to benazepril in controlling proteinuria (CI, −0.035 to 0.268). At Day 180, UP/C compared to baseline in the telmisartan group was significantly lower (−0.05 ± 0.31; P = .016), whereas in the benazepril group the change (−0.02 ± 0.48) was not statistically significant (P = .136). Similar results were obtained at all assessment points with significant decrease in UP/C occurring with telmisartan but not benazepril.Conclusion and Clinical Importance
Both telmisartan and benazepril were well tolerated and safe. Telmisartan proved to be noninferior to benazepril and significantly decreased proteinuria relative to baseline at all assessment points whereas benazepril did not. 相似文献17.
Angela Bacic Márcia M. Kogika Kátia C. Barbaro Cristina S. Iuamoto Denise M. N. Simões Marcelo L. Santoro 《Veterinary clinical pathology / American Society for Veterinary Clinical Pathology》2010,39(2):203-209
Background: Microalbuminuria and hypertension have long been associated with a guarded prognosis in human patients with a variety of diseases. In veterinary medicine, tests for microalbuminuria have been used for detecting early kidney damage, but there is little information regarding its association with high blood pressure in dogs with chronic kidney disease (CKD). Objective: The objective of this study was to evaluate albuminuria and its association with arterial hypertension in dogs with CKD. Methods: Urinary albumin:creatinine (UAC) ratio, urinary protein:creatinine (UPC) ratio, and systolic blood pressure were determined in 39 clinically healthy dogs and 40 dogs with CKD. Results: UAC in dogs with CKD (range, 0.002–7.99; median, 0.38) was statistically different from that of control dogs (range, 0.0005–0.01; median, 0.002). Microalbuminuria (UAC 0.03–0.3) and macroalbuminuria (UAC>0.3) were detected in 32.5% and 50% of dogs with CKD, respectively. Sixty percent (24/40) of dogs with CKD had systolic pressure ≥180 mmHg; in these dogs, UAC ratio (range, 0.006–7.99; median, 1.72) was significantly higher than in dogs with CKD and systolic pressure<180 mmHg (range, 0.002–4.83; median, 0.10). Of hypertensive dogs with CKD, those with UPC>1.0 usually had macroalbuminuria, those with UPC 0.5–1.0 usually had microalbuminuria, and those with UPC<0.5 usually lacked albuminuria. Conclusions: UAC ratio was higher in hypertensive than in normotensive dogs with CKD. Tests designed to detect microalbuminuria may be useful for hypertensive dogs with CKD and a UPC≤1.0 to detect the onset and magnitude of albuminuria. Once macroalbuminuria is overt, the UPC ratio itself can be used for the same purpose. 相似文献
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Kazunori KATAYAMA Makoto TOMATSU Hidetaka FUCHU Masaaki SUGIYAMA Satoshi KAWAHARA Kiyoshi YAMAUCHI Yukio KAWAMURA Michio MUGURUMA 《Animal Science Journal》2003,74(1):53-58
To search for a novel angiotensin I‐converting enzyme (ACE) inhibitory peptide, porcine skeletal troponin was hydrolyzed with pepsin. This hydrolysate showed ACE inhibitory activity, and was applied to various kinds of chromatography to separate an active peptide. Analysis using a protein sequencer identified this peptide as RMLGQTPTK (9mer). This sequence was estimated to occur at the 44–52 position of troponin C, and its 50% inhibitory protein concentration (IC50) was 34 µM. RMLGQTP (7mer), a partial peptide of 9mer, showed activity with an IC50 of 503 µM. RP‐HPLC analysis of a reaction mixture of 9mer and ACE showed that 9mer was slowly hydrolyzed by ACE. On the other hand, 7mer was rapidly hydrolyzed by ACE. Activity of 9mer was reduced as its hydrolysis by ACE proceeded. To estimate the resistance of 9mer to digestive proteases after oral administration, it was reacted with pepsin, α‐chymotrypsin, or trypsin. In each of these reaction mixtures, a significant amount of 9mer remained as a substrate after digestion. Remaining ACE inhibitory activity was close to that of 9mer. These results suggest that 9mer might not be digested after oral administration, because of its relatively high resistance to digestive proteases. Therefore, 9mer might be expected to work well in vivo as an ACE inhibitor. 相似文献
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旨在通过诱导3T3-L1前脂肪细胞转分化为3T3-L1脂肪细胞,探讨二脒那秦（DIZE）内源性激活血管紧张素转化酶2（ACE 2）对细胞脂质沉积的抑制效应及机制。对3T3-L1前脂肪细胞转分化,将分化成功的3T3-L1脂肪细胞分为对照组、DIZE组（12.5、25 μmol·L-1处理）,siACE2组和siACE2+DIZE组（siACE2干扰后+25 μmol·L-1 DIZE）,作用48 h,取上清和细胞进行试验：1）测定细胞上清中三酰甘油和葡萄糖含量;2）油红O染色细胞,并进行定量分析;3） Western blot检测细胞内ACE2和脂肪酸合成关键酶或因子FAS、ACC和SREBP-1c及葡萄糖转运蛋白GLUT4与氧化分解关键酶CS的蛋白表达水平。结果显示：1）成功诱导得到了3T3-L1脂肪细胞,前脂肪细胞诱导至第14天,有95%以上细胞内出现脂滴;2）确定了DIZE作用浓度为12.5和25 μmol·L-1,处理时间为48 h,并用该药物浓度及时间处理3T3-L1脂肪细胞,细胞上清中三酰甘油含量显著降低（P<0.05）,葡萄糖含量显著升高（P<0.05）;25 μmol·L-1 DIZE处理组细胞脂滴减少,siACE2组无显著变化,siACE2+DIZE组脂滴蓄积介于对照组和DIZE组之间; 25 μmol·L-1 DIZE组ACE2蛋白水平显著高于对照组（P<0.05）;siACE2组显著下调（P<0.05）,siACE2+DIZE组较siACE2组无明显变化;3）与对照组相比25 μmol·L-1 DIZE组细胞中FAS、ACC和SREBP-1c蛋白表达下调,siACE2组和siACE2+DIZE组则表达均上调;4）与对照组相比,25 μmol·L-1 DIZE组GLUT4和CS蛋白表达水平显著上调（P<0.05）,siACE2组和siACE2+DIZE组则均显著下调（P<0.05）。综上所述,DIZE处理通过介导脂肪细胞ACE2的内源性激活改善了脂肪细胞的脂肪沉积。其机理：一方面抑制脂质合成;另一方面促进葡萄糖摄取和氧化代谢,两方面协同减少了脂肪沉积。结果提示,ACE2或DIZE可作为防控脂肪沉积发生和发展的潜在靶点或药物。 相似文献