Jennifer L. Steele, DVM Rosemary A. Henik, DVM, MS, DACVIM Rebecca L. Stepien, DVM, MS, DACVIM

Transcription

1 J. L. Steele, R. A. Henik, and R. L. Stepien Effects of Angiotensin-Converting Enzyme Inhibition on Plasma Aldosterone Concentration, Plasma Renin Activity, and Blood Pressure in Spontaneously Hypertensive Cats with Chronic Renal Disease Jennifer L. Steele, DVM Rosemary A. Henik, DVM, MS, DACVIM Rebecca L. Stepien, DVM, MS, DACVIM University of Wisconsin-Madison Department of Medical Sciences 2015 Linden Drive Madison, WI ABSTRACT Hypertension is commonly associated with chronic renal disease in cats, and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) may contribute to the hypertensive state. Angiotensin-converting enzyme (ACE) inhibitors are commonly administered when hypertension is present to decrease plasma concentrations of angiotensin II and aldosterone, which cause vasoconstriction and sodium and water retention, respectively. The study reported here was conducted over a 6- month period to assess the effects of two commonly prescribed ACE inhibitors, enalapril and benazepril, on the activity of the RAAS and blood pressure in 16 spontaneously hypertensive cats with chronic renal disease. Plasma aldosterone and plasma renin activity were not significantly affected by ACE inhibitors in hypertensive cats, and systolic blood pressure did not decrease below 170 mm Hg with ACE inhibitor monotherapy in 14 of 16 cats. These results suggest that continued activation of the RAAS is present in hypertensive cats despite treatment with an ACE inhibitor, and ACE inhibitors should not be used as first-line antihypertensive treatment in hypertensive cats. INTRODUCTION Chronic renal disease in cats is a well-recognized, common clinical syndrome, 1,2 and systemic hypertension is frequently associated with this condition Proposed mechanisms of hypertension associated with chronic renal disease include decreased ability of the diseased kidney to excrete sodium and water, inappropriate activation of the renin-angiotensin-aldosterone system (RAAS), increased production of renopressor substances, decreased renal production of vasodilating substances, and increased concentrations of norepinephrine. 3,4,9,10 Uncontrolled hypertension may cause damage to multiple target organs, including the brain, heart, kidneys, and eyes. 3,6,7,10 The reference range for normal blood pressure in cats may vary with the institution and methodology, but hypertension is usually diagnosed when indirect systolic blood pressure exceeds 160 5,7 or 157

2 Veterinary Therapeutics Vol. 3, No. 2, Summer ,4,6,11 mm Hg. Angiotensin-converting enzyme (ACE) inhibitors, such as enalapril and benazepril, are frequently administered to hypertensive cats with chronic renal disease to decrease vasoconstriction and sodium and water retention Studies in both humans and animals have examined the role of the RAAS in hypertension. 4,16 29 In normal animals, as blood pressure rises to hypertensive levels, plasma renin activity (PRA) decreases, resulting in decreased circulating concentrations of the potent vasoconstrictor, angiotensin II, and the mineralocorticoid, aldosterone. 30,31 If the RAAS is inappropriately activated in hypertension, treatment with an ACE inhibitor would be expected to block the formation of angiotensin II, thereby increasing PRA and decreasing circulating aldosterone concentration. 24,29,32,33 In some patients, however, the escape of aldosterone suppression from the control of ACE inhibitors has been recognized and might account for the poor response to ACE inhibitors in some hypertensive human and veterinary patients. 4,17 20,25,26,29 The purposes of this study were to determine whether appropriate and expected responses to ACE inhibitor treatment occur in hypertensive cats with spontaneous chronic renal disease. If ACE inhibitors were effective in controlling hypertension, then blood pressure would decrease; effective suppression of the RAAS would result in an increase in PRA and a decrease in aldosterone. In addition, hypertensive cats that responded to an ACE inhibitor as a sole antihypertensive agent were monitored for 6 months to determine whether the response was sustained. MATERIALS AND METHODS Cats Sixteen client-owned hypertensive cats with spontaneous chronic renal disease were used in two separate prospective trials evaluating ACE inhibitors as antihypertensive medications. The two studies with different ACE inhibitors were combined for statistical power. In the first study, 12 hypertensive cats were evenly randomized to receive either enalapril (Enacard, Merial, Duluth, GA) (n = 6) or propranolol (n = 6) as the initial treatment. Results of initial blood pressure responses to either drug, as well as baseline neurohormone values, were previously published. 4 In the second study, antihypertensive efficacy of benazepril (Lotensin, Novartis, East Hanover, NJ) was studied in 12 hypertensive cats. One cat died acutely 24 hours after baseline data were collected, and one cat was euthanized during Week 1 due to worsening renal disease, leaving 10 cats from the benazepril study available for evaluation. Of the 16 hypertensive cats receiving only an ACE inhibitor, one (cat 15) was lost to follow-up after Week 2. Blood pressure responses and neurohormone values from the two studies and are presented here. Hypertensive cats ranged in age from 5 to 19 years (mean = 14 years) and included domestic shorthaired (n = 10), domestic mediumhaired (n = 1), domestic longhaired (n = 2), Siamese (n = 1), Tonkinese (n = 1), and Somali (n = 1). Ten cats were spayed females, four were neutered males, and one male and one female each were sexually intact. Ten client-owned, clinically and biochemically normal 6-month- to 11-year-old cats were used to obtain normal reference ranges for aldosterone and PRA (Table 1). Blood Pressure Evaluation Systemic arterial hypertension was defined as indirect systolic blood pressure higher than 170 mm Hg in nonsedated cats using an ultrasonic Doppler method and an appropriately sized neonatal cuff around the median artery in a forelimb. Measurements were made using 158

3 J. L. Steele, R. A. Henik, and R. L. Stepien TABLE 1. Plasma Renin Activity (PRA) and Aldosterone Concentration in Normal Cats PRA Aldosterone Cat Number (ng angiotensin I/ml/hr) (pg/ml) Mean Standard deviation minimal physical restraint either before physical examination or after cage rest to minimize stress-induced increases in blood pressure. Readings were taken over a 5- to 10-minute period until five consecutive similar readings (i.e., less than 10 mm Hg variation) were obtained. The value recorded at each visit was the mean of five readings. Drug Administration Starting oral dosages of ACE inhibitors in hypertensive cats were based on dosages recommended in the veterinary literature (approximately 0.25 to 0.5 mg/kg of body weight/day) (Table 2). 34,35 Enalapril was initially given at 0.36 mg/kg/day (range = 0.18 to 0.81 mg/kg/day) and the dosage of benazepril was 0.64 mg/kg/day (range = 0.24 to 1.07 mg/kg/day). All cats, except Cat 5, received treatment once daily, and the time of administration was determined by the owner. Cat 5 received the daily dose of ACE inhibitor in divided doses every 12 hours. If systolic blood pressure was not suppressed to less than 170 mm Hg at Week 2, the daily dose of ACE inhibitor was doubled for cats having an initial dosage less than 0.8 mg/kg/day, and blood pressure was again evaluated after 2 additional weeks of treatment. Cats receiving initial dosages greater than 0.8 mg/kg/day received additional antihypertensive medications if they were found to be hypertensive at Week 2 and were removed from the study. Cat 13 had the dosage doubled at Week 2 and was rechecked 1 week later because of severe hypertension with retinal hemorrhages. An additional antihypertensive medication was prescribed and the cat was removed from the study. Cat 2 could not tolerate the higher dose of enalapril and was returned to the initial dose. If blood pressure remained above 170 mm Hg at Week 4, an additional antihypertensive drug was prescribed and the animal was excluded from further analysis. All cats that were normotensive at Weeks 2 or 4 were evaluated again at Week 8. If these cats remained normotensive at Week 8, dosing with ACE inhibitor monotherapy was continued and a final evaluation was performed 6 months after initiation of treatment. Values for aldosterone, PRA, and blood pressure reported below are from cats receiving ACE inhibitor as the only antihypertensive treatment. Clinical Evaluations Physical examination, serum biochemical analysis, complete blood cell count (CBC), urinalysis, serum thyroxine concentration, and echocardiography were performed on all cats during the baseline visit. None of the hypertensive cats had elevated serum thyroxine concentrations, but all cats had serum biochemical evidence of renal insufficiency (creatinine level higher than 1.8 mg/dl) and decreased urine specific gravity (less than 1.035). On follow-up 159

4 Veterinary Therapeutics Vol. 3, No. 2, Summer 2002 TABLE 2. Treatment Information for Hypertensive Cats Given Angiotensin-Converting Enzyme (ACE) Inhibitors in Two Studies ACE Inhibitor Dosage (mg/kg/day) Cat Drug Wk 0 Wk 2 Wk 2 Wk 4 Wk 4 Wk 8 1 Enalapril Enalapril /0.24* NR 3 Enalapril Enalapril NR 5 Enalapril Enalapril Benazepril 0.96 AD AD 8 Benazepril NR 9 Benazepril Benazepril Benazepril 0.81 AD AD 12 Benazepril 0.85 AD AD 13 Benazepril AD 14 Benazepril 1.07 AD AD 15 Benazepril 0.39 LTF LTF 16 Benazepril NR Mean (enalapril) Mean (benazepril) *Dosage doubled at Week 2 but was returned to initial dosage when higher dosage was not well tolerated. Dosage doubled at Week 2but required additional antihypertensive medication at Week 3 and was removed from the study. AD = not recorded because additional drug was administered; LTF = lost to follow-up; NR = not recorded due to lack of adequate response to initial or doubled dose. visits, complete physical examination, indirect blood pressure, serum biochemical analysis, CBC (or packed cell volume), urinalysis, and measurements of serum aldosterone and PRA were performed. Owners were encouraged to feed the cats a low-sodium diet if possible, but diet was not controlled. Hormone and Enzyme Assays Blood samples (8 to 10 ml) for plasma collection were obtained by jugular venipuncture between 9 AM and 1 PM and were transferred from syringes into chilled tubes containing EDTA as an anticoagulant. Samples were immediately placed in an ice bath and transferred to a cold centrifuge, where plasma was separated from cells and stored at 70 C. Plasma aldosterone levels were measured using solidphase radioimmunoassay, available commercially as a kit (Coat-A-Count In-vitro Diagnostic Test Kit, Diagnostic Products Corporation, Los Angeles, CA) that had previously been validated in cats. Plasma renin activity was measured as described by Jensen and coworkers. 4 Baseline plasma aldosterone concentrations were measured in all 16 hypertensive cats, whereas baseline PRA was measured in 15 cats due to insufficient sample volume for one cat. Plasma aldosterone and PRA were measured in all cats after 2 weeks of ACE inhibitor treatment, in six cats that responded to ACE inhibitor treatment at the 8-week evaluation (i.e., systolic blood pressure 170 mm Hg or lower), and in two cats that were normoten- 160

5 J. L. Steele, R. A. Henik, and R. L. Stepien TABLE 3. Noninvasive Systolic Blood Pressure, Plasma Renin Activity (PRA), and Plasma Aldosterone Concentration in Hypertensive Cats after Treatment with Angiotensin-Converting Enzyme Inhibitors Blood Pressure (mm Hg) PRA (ng angiotensin I/ml/hr) Aldosterone (pg/ml) Cat Baseline Wk 2 Wk 4 Wk 8 Baseline Wk 2 Wk 8 Baseline Wk 2 Wk NR NE NE NE QNS NE NE NE NR AD NE NE NE NE NE NE NR AD NE NE NE NE NE NE AD NE NE NE AD NE NE NE NE NE NE NE NE NE NE Mean SD AD = not evaluated because additional antihypertensive medication was added after the initial dose of ACE inhibitor was inadequate to control blood pressure; NE = not evaluated due to lack of adequate response; NR = not evaluated because blood pressure measured during Wk 2 was below 170 mm Hg; QNS = sample quantity insufficient for testing. sive and were receiving only ACE inhibitor treatment at the 6-month evaluation. Statistical Analysis All pairwise comparisons were conducted using a Mann-Whitney U test. Group mean aldosterone concentrations and PRA were compared between normal reference cats and hypertensive cats at baseline. Mean aldosterone concentrations, PRA, and blood pressure in hypertensive cats at Weeks 2 and 8 were compared with their baseline values. Cat 3 was excluded from pairwise comparisons for PRA between baseline and Week 2 and between baseline and Week 8 due to insufficient sample volume at baseline. The lower limit of detection for aldosterone was 18 pg/ml; therefore, values below this limit were reported as 18 pg/ml for statistical purposes. Likewise, the lower limit of detection of the PRA assay was 0.01 ng angiotensin I/ml/hr, so values measuring below this level were reported as 0.01 ng angiotensin I/ml/hr. Six-month values were not analyzed statistically due to the low number of cats remaining in the study (n = 2). P values of.05 or less were considered significant. RESULTS Plasma Hormone Concentrations Aldosterone The mean aldosterone level for normal cats (n = 10) was 55.7 pg/ml, and the reference 161

6 Veterinary Therapeutics Vol. 3, No. 2, Summer 2002 range (mean ± 2 SD) was 7.08 to pg/ml (Table 1). The mean aldosterone concentration in hypertensive cats at baseline (153.3 ± pg/ml) was significantly higher (P =.025) than the mean in normal cats (Table 3). Mean aldosterone values for hypertensive cats at Week 2 (167.3 ± pg/ml) and Week 8 (80.6 ± 59.2 pg/ml) were not significantly different from baseline. Aldosterone concentrations were above the reference range in nine cats (56%) at baseline and, despite treatment with an ACE inhibitor, remained above the reference range for eight (50%) cats at Week 2, two of six cats (33%) at Week 8, and one of the two remaining cats at 6 months (Table 3). Plasma Renin Activity Mean PRA in normal cats was 2.82 ng angiotensin I/ml/hr, and the reference range (mean ± 2 SD) was 0.34 to 5.30 ng angiotensin I/ml/hr (Table 1). Mean PRA in hypertensive cats at baseline (1.89 ± 3.30 ng angiotensin I/ml/hr) was significantly lower than the mean in normal cats (P =.014; Table 3). Mean PRA after 2 weeks (3.28 ± 5.07 ng angiotensin I/ml/hr) and after 8 weeks (5.18 ± 4.74 ng angiotensin I/ml/hr; n = 6) of treatment with an ACE inhibitor was not significantly different from the mean baseline PRA. Eight of 15 hypertensive cats had a PRA value within or above the reference range at baseline, suggesting activation of the RAAS. Blood Pressure Individual baseline blood pressure in the 16 hypertensive cats ranged from 178 to 260 mm Hg (mean = 206 mm Hg; Table 3). After 2 weeks of treatment with an ACE inhibitor, three (19%) cats showed an adequate clinical response, with blood pressure readings of 170 mm Hg or lower; however, 13 cats (81%) did not have an adequate response and the dosage of ACE inhibitor was doubled in seven of them. Of these seven cats, four (57%) failed to show an adequate blood pressure response at Week 4; these cats received an additional antihypertensive drug and were excluded from further analysis. Six cats (three at the original dosage and three at the increased dosage) were receiving only ACE inhibitor treatment at the 8-week evaluation. At that time, four of the six cats that initially responded to ACE inhibitor treatment (either at the original or doubled dosage) remained normotensive. However, by the 6-month follow-up, only two cats (one treated with enalapril and one treated with benazepril) remained normotensive while receiving an ACE inhibitor as the sole antihypertensive agent. DISCUSSION Previous studies of ACE inhibitors in cats have evaluated the reduction of plasma ACE in normal 34,35 cats and nonhypertensive cats with polycystic renal disease. 23 Enalapril at 0.25 to 0.5 mg/kg body weight produced a 95% reduction in ACE 2 to 4 hours after oral dosing in normal cats, and these values remained below 50% of control values for 2 to 3 days. 35 Benazepril at 0.25, 0.5, or 1.0 mg/kg body weight caused a 100% reduction in ACE at peak effect (2 hours) in normal cats, and ACE remained at or below 90% of control values at 24 hours. 34 Normotensive cats with polycystic renal disease had a reduction in blood pressure (compared with baseline measurements) after 7 days of enalapril 23 ; however, measurements at both times were within the reference range, and acclimatization to the environment and study conditions cannot be ruled out as a source of blood pressure reduction. An abstract evaluating benazepril in hypertensive cats with renal disease suggested antihypertensive effects; however, blood pressure data were not given. 36 Although plasma ACE may decrease in re- 162

7 J. L. Steele, R. A. Henik, and R. L. Stepien sponse to ACE inhibitors, this may not translate into a clinically measurable response (i.e., reduction in blood pressure). Likewise, the numerous checks and balances of neurohormonal systems may prevent a measurable decrease in hormones necessary to maintain intravascular volume (i.e., aldosterone). Although aldosterone production is assumed to decrease with ACE inhibitors, 29,33 studies in humans have shown that aldosterone can escape this inhibition, resulting in levels being similar to or higher than at baseline. 17,18,20,26 Numerous mechanisms have been proposed to explain the apparent escape of aldosterone from ACE inhibition, including other conversion pathways of angiotensin I to angiotensin II that are not affected by ACE inhibitors (e.g., chymase- 28 or tonin- 20 dependent angiotensin II production). Alternatively, although ACE concentrations may decrease with ACE inhibitors, there may be sufficient ACE to convert angiotensin I to angiotensin II due to high background concentrations of angiotensin I. 20 Other explanations for aldosterone escape include the existence of basal and pulsatile aldosterone secretion not influenced by the renin-angiotensin axis, 18 or decreased concentrations of atrial natriuretic peptide that no longer inhibit aldosterone production in the zona glomerulosa. 19 In the present study, 11 of 16 (69%) hypertensive cats receiving an ACE inhibitor had increased aldosterone at Week 2 compared with baseline values, and four of six (67%) cats had increased aldosterone at Week 8 compared with Week 2. Likewise, mean aldosterone did not significantly decrease following 7 days of treatment with enalapril (0.5 mg/kg/day) in six cats with autosomal dominant polycystic kidney disease. 23 The reference range of aldosterone (7.08 to pg/ml) determined in this study is similar to the established reference range of 70 to 140 pg/ml used by a veterinary diagnostic laboratory (Endocrine Diagnostic Services, Michigan State University, Lansing, MI) and the reference range of to pg/ml determined by Jensen and coworkers. 4 A recent report by Yu and Morris lists the upper limit for aldosterone, defined by the 95 th percentile in 148 normal cats, as 700 pmol/l, equivalent to pg/ml. 37 A wider reference range of 42 to 352 pg/ml, obtained from evaluation of six cats, is listed by Dow and coworkers. 38 Steroid hormones such as aldosterone tend to be stable in plasma, and the commercially available kit used for radioimmunoassay in the present study has been used in multiple studies. 4,23,37,38 Sampling times in this study were not uniform relative to drug administration, but cats do not exhibit circadian rhythm of aldosterone secretion 37 and neither basal nor pulsatile aldosterone secretion in humans is affected by intravenous enalaprilat administration. 18 The reference range for PRA (0.34 to 5.30 ng angiotensin I/ml/hr) used in this study is similar to a previously reported range of to ng angiotensin I/ml/hr. 4 One investigator reported a reference range obtained from six healthy older cats to be 0.42 to ng angiotensin I/ml/hr. 38 Peptides are labile and PRA results may vary among laboratories depending on specific inhibitors in the assay, causing some difficulty in comparing results among different laboratories. Since an appropriate response to hypertension is decreased PRA, eight of 15 cats in the present study showed activation of the RAAS based on normal to increased baseline PRA. Following treatment with an ACE inhibitor, plasma renin activity increased appropriately in 10 cats, was relatively unchanged in three cats, and decreased in two cats compared with baseline values. The dosage of ACE inhibitor did not determine PRA response; therefore, sample handling, poor owner compliance, or individual drug response should be considered as possible causes of this unexpected finding. 163

8 Veterinary Therapeutics Vol. 3, No. 2, Summer 2002 In the majority of the cats in this study, ACE inhibitors as a monotherapy did not provide sustained antihypertensive effects. Only six of 16 cats initially exhibited an adequate antihypertensive response to treatment with an ACE inhibitor; four remained controlled at 8 weeks; and only two of the 16 original cats remained controlled at 6 months. Although poor owner compliance could have resulted in a lack of an adequate blood pressure response to ACE inhibitor treatment, owner compliance was considered good to excellent. Measurement of ACE activity concomitantly with aldosterone and PRA would have been helpful to document drug activity. Since prior reports of the activity of ACE inhibitors have monitored cats for one 23 to two 4 weeks, the present study monitored blood pressure response for 6 months to allow evaluation of a sustained response, or lack thereof, and the relationship of aldosterone to blood pressure. Based on information obtained in this study, it is important to monitor hypertensive cats frequently, since initial response may not be long lasting. One also needs to take into account the pulsatility of blood pressure, the white coat effect, 39 and spurious measurements, however, so that cats will not be inappropriately medicated. Hormonal assessment of hypertensive cats that did respond to ACE inhibitor treatment would suggest that a decrease in blood pressure is not associated with a decrease in aldosterone. Therefore, aldosterone may be partly or not at all contributory to hypertension in some cats. Although it has been suggested that hypertensive cats may require a higher dose of ACE inhibitor, 12 only one of five cats receiving an initial dose greater than 0.8 mg/kg/day had an adequate response. If ACE inhibitors are indicated for treatment of chronic renal disease, then additional studies using higher doses of ACE inhibitors may be necessary in hypertensive cats. There are other indications (e.g., proteinuria) for the use of ACE inhibitors in chronic renal disease that make them useful as adjunctive therapy. 12 Proteinuria tends to be rare in chronic renal disease in cats, and only two of 15 cats in this study had an initial protein:creatinine concentration ratio above 0.5 (unpublished data). This clinical study is limited by a low number of patients on varying diets and in different stages of chronic renal disease. Histopathologic evaluation of the kidneys was not obtained by ultrasound-guided biopsy due to the inherent morbidity of the procedure in azotemic cats. In addition, variability in neurohormones may exist, but plasma samples were analyzed in bulk to avoid unnecessary variability in results. Although the study did not include a group of hypertensive cats treated with a vehicle control, a placebo-controlled, double-blinded study has previously evaluated blood pressure response using amlodipine. 40 In that study, blood pressure did not change in the placebo group. The authors also feel that the standard of care in client-owned cats is to provide treatment for hypertension rather than risk development of serious complications by administering placebo. Large standard deviations in neurohormonal reference data may obscure small but real responses to treatment with an ACE inhibitor. Blood pressure measurements in cats are known to fluctuate, but the circumstances and methods in this study accurately reflect typical blood pressure measurement in clinical practice. Therefore, blood pressure findings in this study might be expected to represent the typical data upon which clinicians routinely make therapeutic decisions. CONCLUSION If increased aldosterone concentrations contribute to hypertension, effective suppression of the RAAS with ACE inhibitors would be expected to result in increased PRA, decreased al- 164

9 J. L. Steele, R. A. Henik, and R. L. Stepien dosterone concentration, and decreased blood pressure. These expected neurohormonal and blood pressure effects were not seen in this group of hypertensive cats after treatment with ACE inhibitors. Possible explanations for the lack of neurohormonal and antihypertensive effects to ACE inhibitors include inadequate dosage, a reduction in aldosterone degradation, or an increase in aldosterone production from an alternate pathway (i.e., aldosterone escape ). The majority of cats in this study with hypertension associated with chronic renal insufficiency had elevated aldosterone concentrations. Continued RAAS activation in the presence of ACE inhibitor treatment may contribute to inadequate blood pressure responses seen in these cats, or hypertension may be controlled by factors other than the RAAS. Further studies are indicated to investigate whether specific competitive aldosterone inhibitors (e.g., spironolactone) would provide benefit in the control of feline hypertension. REFERENCES 1. Brown SA: Evaluation of chronic renal disease: A staged approach. Compend Contin Educ Pract Vet 21: , Lulich JP, Osborne CA, O Brien TD, et al: Feline renal failure: Questions, answers, questions. Compend Contin Educ Pract Vet 14: , Dukes J: Hypertension: A review of the mechanisms, manifestations and management. J Small Anim Pract 33: , Jensen J, Henik RA, Brownfield M, et al: Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease. Am J Vet Res 58: , Stiles J, Polzin DJ, Bistner SI: The prevalence of retinopathy in cats with systemic hypertension and chronic renal failure or hyperthyroidism. J Am Anim Hosp Assoc 30: , Henik RA: Diagnosis and treatment of feline hypertension. Compend Contin Educ Pract Vet 19: , Littman MP: Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 8:79 86, Bodey AR, Sansom J: Epidemiological study of blood pressure in domestic cats. J Small Anim Pract 39: , Kobayashi DL, Peterson ME, Graves TK, et al: Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 4:58 62, Ross LA: Hypertension and chronic renal failure. Semin Vet Med Surg (Small Anim) 7: , Turner JL, Brogdon JD, Lees GE, et al: Idiopathic hypertension in a cat with secondary hypertensive retinopathy associated with a high salt diet. J Am Anim Hosp Assoc 26: , Brown SA, Henik RA: Therapy for systemic hypertension in dogs and cats. In: Bonagura JD, ed. Current Veterinary Therapy XIII, Small Animal Practice. Philadelphia: WB Saunders; 2000: Grauer GF: Renal failure. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine. 2 nd ed. St. Louis: Mosby; 1998: Polzin DJ, Osborne CA, Jacob F, Ross S: Chronic renal failure. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Philadelphia: WB Saunders; 2000: Ross LA: Pathophysiology and management of systemic hypertension associated with renal dysfunction. In: Osborne CA, Finco DR, eds. Canine and Feline Nephrology and Urology. Baltimore: Williams & Wilkins; 1995: Melby JC: The renin-angiotensin-aldosterone complex. Am J Med 81(suppl 4C):8 12, Pitt B: Escape of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implications for therapy. Cardiovasc Drugs Ther 9: , Fliser D, Veldhuis JD, Dikow R, et al: Effects of acute ACE inhibition on pulsatile renin and aldosterone secretion and their synchrony. Hypertension 32: , Sala C, Bragato R, Ardeleani G, et al: Reciprocal changes in atrial natriuretic factor and aldosterone during angiotensin converting enzyme inhibition in man. J Hypertension 7(suppl 6):S240 S241, Reams GP, Bauer JH, Gaddy P: Use of the converting enzyme inhibitor enalapril in renovascular hypertension; effect on blood pressure, renal function, and the renin-angiotensin-aldosterone system. Hypertension 8: , Hall JE: Control of blood pressure by the renin-angiotensin-aldosterone system. Clin Cardiol 14(suppl IV):6 21, Häggström J, Hansson K, Karlberg BE, et al: Effects of long-term treatment with enalapril or hydralazine 165

10 Veterinary Therapeutics Vol. 3, No. 2, Summer 2002 on the renin-angiotensin-aldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation. Am J Vet Res 57: , Miller RH, Lehmkuhl LB, Smeak DD, et al: Effect of enalapril on blood pressure, renal function, and the renin-angiotensin-aldosterone system in cats with autosomal dominant polycystic kidney disease. Am J Vet Res 60: , Abdelrahman AM, Burrell LM, Johnston CI: Blockade of the renin-angiotensin system at different sites: Effect on renin, angiotensin, and aldosterone. J Hypertension 11(suppl 3):S23 S26, Struthers AD: Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J 16(suppl N): , MacFadyen RJ, Lee AFC, Morton JJ, et al: How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 82:57 61, Pedersen HD, Koch J, Poulsen K, et al: Activation of the renin-angiotensin system in dogs with asymptomatic and mildly symptomatic mitral valvular insufficiency. J Vet Intern Med 9: , Liao Y, Husain A: The chymase-angiotensin system in humans: biochemistry, molecular biology and potential role in cardiovascular diseases. Can J Cardiol 11 (suppl F):13F 19F, Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity in patients with severe heart failure. N Engl J Med 341: , Guyton AC, Hall JE: Dominant role of the kidneys in long-term regulation of arterial pressure and in hypertension: The integrated system for pressure control. In: Guyton AC, Hall JE, eds. Textbook of Medical Physiology. Philadelphia: WB Saunders; 1996: Verlander JW: Glomerular filtration. In: Cunningham JG, ed. Textbook of Veterinary Physiology. Philadelphia: WB Saunders; 1997: Plumb DC: Veterinary Drug Handbook. Ames, IA: Iowa State University Press; 1999:74 75, Jackson EK, Garrison JC: Renin and angiotensin. In: Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman and Gilman s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 1996: King JN, Humbert-Droz E, Maurer M: Pharmacokinetics of benazepril and inhibition of plasma ACE activity in cats. Proc 14 th Am Coll Vet Int Med Forum 45, Sanders N, Hamlin R, Buffington T, et al: Effects of enalapril on healthy cats. Proc 10 th Am Coll Vet Int Med Forum 822, Tilley L, King JN, Humbert-Droz E, et al: Benazepril activity in cats: Inhibition of plasma ACE and efficacy in the treatment of hypertension. Proc 14 th Am Coll Vet Int Med Forum 745, Yu S, Morris JG: Plasma aldosterone concentration of cats. Vet J 155:63 68, Dow SW, Fettman MJ, LeCouteur RA, et al: Potassium depletion in cats: Renal and dietary influences. JAVMA 191: , Belew AM, Barlett T, Brown SA: Evaluation of the whitecoat effect in cats. J Vet Intern Med 13: , Snyder PS: Amlodipine: A randomized, blinded clinical trial in 9 cats with systemic hypertension. J Vet Intern Med 12: ,