U ing consequence^.^-^ Clinical signs referable to systemic

~~~ J Vet Intern Med 1998;12:157-162 Amlodipine: A Randomized, Blinded Clinical Trial in 9 Cats with Systemic Hypertension Patti S. Snyder The efficacy of amlodipine (AML) was tested in hypertensive cats in a placebo-controlled, randomized, blinded clinical trial. Five cats were randomized to receive 0.625 mg AML once daily and 4 cats to receive placebo (PLA) once daily. The average systolic blood pressure (SBP) recorded by the Doppler method on day 0 was 212 t 21 mm Hg in the AML group and 216 2 32 mm Hg in the PLA group. On day 7, the cats receiving AML had a significantly lower average daily SBP (160 2 30 mm Hg) but SBP in the PLA group was unchanged (207 2 3 1 mm Hg). On day 7, all cats receiving PLA and one cat receiving AML were crossed over to the other group because of inadequate response. Blood pressure did not decrease adequately in 3 cats by day 14 (7 days of PLA and 7 days AML) and the treatment code was broken. Each of these cats was subsequently administered 1.25 mg AML daily. Cats requiring 1.25 mg AML once daily (6.1 kg 2 0.7 kg) weighed significantly more than cats that responded to 0.625 mg AML once daily (4.1 i- 0.7 kg). The average daily SBP recorded in the 6 cats that completed the study was significantly lower after 16 weeks of treatment (152 % 14 mm Hg) compared to day 0 (221 t 24 mm Hg). Three cats were euthanized before completion of the study. All 3 cats were responders to AML on day 7. SBPs measured 24 hours after AML administration were similar to the average daily SBP, suggesting that AML effectively controlled SBP for a 24-hour period. AML was shown to be an effective once-daily antihypertensive agent when administered to cats at a dosage of 0.18 2 0.03 mg/kg sid. Key words: Calcium channel blockers; Feline renal failure. ncontrolled systemic hypertension can have devastat- U ing consequence^.^-^ Clinical signs referable to systemic hypertension in cats include blindness due to intraocular hemorrhage or retinal detachment, cardiac murmurs and arrhythmias, and neurologic signs such as seizures, ataxia, collapse, and paresis.'-5 Successful management of cats with systemic hypertension requires early recognition of clinical signs, confirmation of abnormal blood pressure, and treatment with an effective antihypertensive agent. A variety of drugs including diuretics, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, alpha-adrenergic blocking agents, and calcium channel blockers have been tried with mixed results. The necessity for multiple drug therapy or frequent drug administration leads to inconsistent owner compliance further complicating the management of affected cats.zj.h Although a few clinical reports have described antihypertensive therapy in hypertensive cats, no controlled clinical trials have been conducted in cat~.'-~."~ A pparent reports of success are limited by infrequent blood pressure measurements and failure to document the activity of the drugs for 24 hours.1.2.h Systemic hypertension in animals usually is secondary to other diseases such as renal disease, hyperadrenocorticism, hyperaldosteronism, hyperthyroidism, and pheochromocytoma.2,x Primary or essential hypertension is rare. The most common causes of systemic hypertension in cats are renal insufficiency and hyperthyroidism.' Because hypertension often resolves with treatment of hyperthyroidism, many of the cats requiring long-term medical control of hypertension are those with renal Therefore, medi- From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL. Reprint requests: Patti Snyder, DVM, MS, Box 100126 HSC, College of Veterinay Medicine, University of Florida, Gainesville, FL 32610-0126; e-mail: snyder@mail.vetmed.ujl.edu. Accepted November 17, 1997. Copyright 0 I998 by the American College of Veterinuty Internal Medicine 0891-6640/98/1203-0005/$3.00/0 cations administered to cats with systemic hypertension must be safe in cats with renal insufficiency. The purpose of this study was to determine the efficacy of the dihydropyridine calcium channel blocker amlodipine (AML) (Norvasc, Pfizer, New York, NY) as a once-daily, single agent, antihypertensive treatment for cats with systemic hypertension. Many cats with systemic hypertension have renal insufficiency, so the effect of AML on renal function (blood urea nitrogen concentration [BUN] and serum creatinine concentration [Cr] also was evaluated. Materials and Methods Criteria for Patient Selection. All cats were client-owned and the owners consented to participation in the clinical trial. Only cats expected to live for more than 16 weeks were accepted into the study. The study was reviewed and approved by the University of Florida Clinical Research Committee on Animal Use. Cats were included in the study if their average systolic blood pressure (SBP) measured indirectly by the Doppler method (Ultrasonic Doppler Flow Detector, Model 8 1 1 -B, Parks Medical Electronics, Inc, Aloha, OR) was greater than 170 mm Hg when measured at hours 0, 3, 6, 9, 12, 21, and 24 and if they had a normal serum thyroxine concentration. Cats admitted to the study had not received any antihypertensive medication for the previous month. Serum biochemical profile, CBC, and urinalysis were performed on each cat at the time of admission (day 0), after 7 days (day 7), and after 16 weeks (week 16) of treatment. Serum thyroxine concentrations were measured on day 0 and week 16. SBPs were measured indirectly by the Doppler flowmeter method at times 0, 3, 6, 9, 12, 21, and 24 hours on day 0. Cats then were randomized to receive either 0.625 mg AML or placebo (PLA) orally once daily in a capsule form. The owners were instructed to give the test material at the same time each morning (between 600 and 9:OO AM). The cats were returned on day 7 and the test material was given by the investigator at time 0. Blood pressure measurements were repeated in a similar fashion as performed on day 0. If the average daily SBP on day 7 was <I70 mm Hg or if it had declined by at least 15% of the average day 0 recordings, the cats remained in the same treatment group. If the average SBP had not declined by at least 15% or was not <I70 mm Hg, the cat was switched to the other group without breaking the treatment code. Cats that were switched to the alternate treatment group were reevaluated on day 14 of study (ie, after 7 days of the new therapy). Blood pressure measurements were repeated in a

~~ ~ I58 Snyder 300 T I 100 1 i--- I - t - 0 3 6 9 12 Time (Hours) t t i 15 18 21 24 Fig 1. Systolic blood pressure recordings for 5 cats (mean 2 standard error of the mean [SEMI) before (day 0: W) and after 7 days (day 7: 0) of 0.625 mg amlodipine PO sid (administered at time 0). -i similar manner as performed on day 0 and day 7 in these cats. All responding cats were evaluated after 16 weeks of treatment in a way identical to day 0 and day 7. If the average daily SBP still was > 170 mm Hg after 7 days of the alternate treatment, the treatment code was broken and the cat was placed on 1.25 mg AML once daily and similar weekly follow-up evaluations were requested. If the average daily SBP remained >I70 mm Hg after 2 weeks of 1.25 mg AML daily, the cat was removed from the study and other medications administered in an attempt to control hypertension. Cats that received 1.25 mg AML also were studied after 16 weeks of treatment in an identical manner as on day 0 and day 7. Drugs were administered once daily (in the morning) at the same time each test day. Cats were offered their normal diet and water was offered ad libitum. No attempt was made to synchronize feeding to administration of medication. Blood Pressure Measurements. Systolic arterial blood pressures were measured indirectly using an ultrasonic Doppler flow detector."'." Cats were held gently in sternal recumbency and the foreleg extended from behind the elbow to provide access to the palmar aspect of the carpus. A neonatal #2 or #3 blood pressure cuff (Critikon, Tampa, FL) was placed just above the carpus. The cuff with a width that most closely approximated 40% the limb circumference was used throughout the study."'." Coupling gel was applied to the palmar aspect of the carpus and the transducer. The transducer was placed distal to the cuff and positioned on the palmar aspect of the metacarpal region until a clear arterial pulse signal was heard from the common digital branch of the radial artery. Systolic blood pressure was measured as previously described."' Five measurements were obtained over approximately 5 minutes, recorded, and later averaged to obtain a single measurement for that time. The cats were kept in a quiet environment devoid of other animal contact on the recording days. Statistical Analysis. The results are expressed as mean 2 standard deviation and range. Paired t-tests were performed within groups (day 0 versus day 7 and day 0 versus week 16) to compare results and between-group (AML versus PLA) comparisons were made using unpaired t-tests. Significance was defined as P 5.05. To determine if a relationship between body weight and initial presenting SBP existed, Pearson's correlation coefficient (r) was calculated for these variables. To demonstrate the reproducibility of the 5 sequential SBPs averaged to obtain a single SBP, the coefficient of variation (CV = standard deviation of the 5 individual measurements/mean SBP measurement X 100) was calculated for each cat for each time period (0, 3, 6, 9, 12, 21, and 24 hours) on each testing day (day 0, day 7, and week 16). Results Nine cats with a mean age of 14 2 4 years (range 6-18 years) and mean weight of 4.8 5 1.3 kg (range 3.4-7.0 kg) met the criteria for the study. This group included 5 neutered males, 4 neutered females, and 1 intact female. These cats included 6 mixed breeds, 1 Siamese, 1 Persian, and 1 American Shorthair. All 9 cats had been presented for suspected blindness and on physical examination had retinal detachments with or without severe retinal hemorrhage. Eight cats had not received any antihypertensive treatment. One cat had been given propranolol (dose unknown) 3 months before entry into the study because of retinal detachment, blindness, and suspected systemic hypertension. No blood pressure measurements were performed at that time and the medication had been discontinued after 1 month by the owner because the cat remained blind. Five cats (4.5 5 0.8 kg, range 3.6-5.4 kg) received AML (0.14? 0.03 mgkg, range 0.11-0.17 mg/kg/day) as the initial test material. The average daily SBP decreased significantly (P =,003) by 1 week (Fig 1; day 0: 212 5 21 mm Hg [range 188-233 mm Hg] versus day 7: 160 5 30 mm Hg [range 130-200 mm Hg]). Four of the 5 cats' average daily SBP decreased to <170 mm Hg. One cat was switched to PLA after 1 week because of an inadequate response to AML (a 10.8% decrease in average daily SBP). All 4 cats initially given PLA (5.1 5 1.8 kg, range 3.4-7.0 kg) were switched to AML after 7 days because the average daily SBP did not decrease (P =.162) (Fig 2; day 0: 216 5 32 mm Hg [range 187-260 mm Hg] versus day 7: 207? 31 mm Hg [range 180-249 mm Hg]). The percentage change in average daily SBP in cats receiving PLA for 7 days ranged from a 1.4% increase to a 10.8% decrease. Three cats failed to respond to either PLA or 0.625 mg AML and after 14 days (7 days of AML and 7 days PLA) the treatment code was broken. Each of these cats subsequently was given 1.25 mg AML once daily. Although weekly reevaluation of treatment response was requested, the clients returned their cats infrequently and only sporadic blood pressures were performed until week 16. The 3 cats

I Amlodipine Clinical Trial 159 250 J 150-100 - -- ~ I ~~ --,-, -i 0 3 6 9 12 15 16 21 24 Time (Hours) Fig 2. Systolic blood pressure recordings for 4 cats (mean 2 standard error of the mean [SEMI) before (day 0 W) and after 7 days (day 7. A) of placebo PO sid (administered at time 0) requiring 1.25 mg AML weighed significantly more (6.1 t 0.7 kg, range 5.4-7.0 kg) than cats responding to 0.625 mg AML (4.1 t 0.7 kg, range 3.4-5.1 kg) (P =.003). The average daily SBP on admission to the study (day 0) in these 3 cats was 234 5 24 mm Hg (range 214-260 mm Hg). The average daily SBP of the other 6 cats on day 0 of the study was 204 2 19 mm Hg (range 187-233 mm Hg). To determine whether the initial SBP was higher in cats weighing more, a Pearson s correlation coefficient was calculated for body weight and initial average daily SBP on day 0. Based upon the results (Y = 0.34, r2 = O.ll), 11% of the variation in SBP could be explained by body weight. However, because of the small sample size, the ability to find a significant correlation between these 2 variables is not good because the correlation would need to be 0.89 or better in order to detect a difference. The average daily blood pressure for all 6 cats that completed the study (and received either 0.625 mg AML or 1.25 mg AML) decreased significantly from 221? 24 mm Hg (range 188-260 mm Hg) on day 0 to 152 t 14 mm Hg (range 127-166 mm Hg) at week 16 (Fig 3; P <.0001). All cats completing 16 weeks of treatment had an average daily SBP of <170 mm Hg. The average daily SBP in the 3 cats that received 1.25 mg AML during week 16 (155? 10.02 mm Hg, range 146-166 mm Hg) appeared to be similar to that in the 3 cats that received 0.625 mg AML (148 t 18.23 mm Hg, range 127-162 mm Hg); however, the small sample size makes statistical comparison less meaningful. The SBP obtained 24 hours after administration of AML was not statistically different from the average daily SBP for cats receiving AML for 7 days (n = 5) or 16 weeks (n = 6) (Table 1). At week 16, the AML dose administered to all cats (n = 6) was 0.18 2 0.03 mg/kg sid (range 0.12-0.21 mgkg). With the exception of 1 time period for 1 cat (hour 21, week 16), the coefficient of variation of the 5 sequential SBP measurements obtained for each cat for each testing period (0, 3, 6, 9, 12, 21, and 24 hours) was less than 7% (Table 2) and the mean coefficient of variation was less than 4%. Three cats had a [Cr] 2 2 mg/dl upon admission (all 300 n m u u ) l 150-100- a +- _t I 0 3 6 9 12 15 16 21 24 Time (Hours) Fig 3. Systolic blood pressure recordings for 6 cats (mean i standard error of the mean [SEMI) before (day 0 W) and after 16 weeks (week 16 +) of 0 625 mg or 1 25 mg amlodipine PO sid (administered at time 0)

160 Snyder Table 1. Comparison of the systolic blood pressure (SBP) (mean * standard deviation [range]) obtained 24 hours after administration of amlodipine (AML) to the average daily SBP for day 7 and week 16. No significant differences were observed. Day 7 Week 16 (n = 5) (n = 6) SBP 24 hours after AML 156 5 26 155 2 15 administration (mm Hg) (130-193) (I 30-1 72) Average daily SBP 160 + 30 152 2 14 (mm Hg) (130-200) (127-166) cats: 2.0 -C 1.2 mg/dl, range 1.1-4.9 mg/dl). Two cats with normal [Cr] had a urine specific gravity of (1.020. Serum thyroxine concentrations (day 0: 2.0 2 0.7 pg/dl, range 1.1-3.1 pg/dl; and week 16: 1.6 2 0.2 pg/dl, range 1.3-2.1 kg/dl) were normal in all cats during the trial. [Cr] and [BUN] did not change in 5 cats given AML for 7 days or in 6 cats that received AML for I6 weeks (Table 3). The average body weight of the 6 cats was unchanged during the study (Table 3). No cat was removed from the study because of inadequate treatment response. Three cats were euthanized before completion of the study: 1 for neoplasia suspected to be of mammary gland origin at week 4; 1 for worsening azotemia, inappetance, and weight loss at week 14; and 1 for inappropriate urination (of several years duration) at week 13. All 3 cats were responders on day 7. Discussion AML was evaluated for its antihypertensive effect because of the inconsistent results obtained when other antihypertensive agents were given to hypertensive cat^.^-^ AML belongs to the dihydropyridine subclass of calcium channel blockers. AML inhibits calcium influx into cardiac and vascular smooth muscle via the long-lasting (Ltype) calcium channe1.i2 The main site of action of AML is the peripheral vasculature but AML also has some effect on the coronary vascular bed. Unlike the calcium channel blockers diltiazem and verapamil, AML has no significant cardiodepressive effects and minimal effects on electrical conduction within the heart. AML currently is licensed for use in humans with systemic hypertension or angina. In humans, AML has a gradual onset and long duration of action, making it suitable for once-daily oral administration.i7-l5 In the current study, the SBP measurements obtained 24 hours after AML was administered were similar to the daily average of the SBP measurements. This suggests that the duration of action in the cat is at least 24 hours. A significant decline in SBP was observed after 7 days of treatment with AML; therefore, follow-up evaluations can be scheduled 1 week after initiating AML to reliably evaluate for an adequate response. The dose found to be effective in decreasing SBP to <170 mm Hg was 0.18 -C 0.03 mgkg. This dose is comparable to that used previously in hypertensive The plasma half-life of AML is approximately 34-45 hours in humans, 24 hours in dogs, and 3 hours in rat^.'^.'^ The pharmacokinetic properties of AML have not been de- Table 2. Coefficient of variation of the 5 individual systolic blood pressures averaged at each time period (0, 3, 6, 9, 12, 21, and 24 hours) for all cats on day 0, day 7, and week 16. Number Time of Cats Mean (%) SD (7o) Range (7%) Day 0 9 2.8 1.4 0-6.6 Day I 9 2.7 1.3 0-6.3 Week 16 6 3.4 2.0 0.6-1 I.8 SD, standard deviation termined for the cat. Although no equivalent pharmacokinetic studies exist in veterinary medicine, renal disease apparently does not alter the pharmacokinetic properties of AML in humans.lx-zo Hypertension occurs commonly in cats with hyperthyroidism and chronic renal failure. Cats with hyperthyroidism were excluded from this study because hypertension associated with hyperthyroidism often resolves with treatment of the underlying condition. Three cats in this study were azotemic and 2 other cats had minimally concentrated urine. Renal insufficiency was suspected as the cause of hypertension in these cats. Essential hypertension and other secondary causes of hypertension such as hyperaldosteronism, pheochromocytoma, and hyperadrenocorticism were not excluded in the remaining cats. Only 1 studyy has reported the expected range for SBP (measured indirectly) in clinically normal, awake cats (1 18 5 11 mm Hg) but most investigators are reluctant to consider a cat hypertensive unless its sustained SBP exceeds 170 mm Hg.1-4,6.x For the purposes of this study, hypertension was defined as a daily average SBP of > 170 mm Hg. The presenting clinical signs as well as persistent SBP of >170 mm Hg were consistent with a diagnosis of systemic hypertension in the 9 cats in this study. SBP was measured serially over 24 hours on each testing day in all cats rather than obtaining single SBP measurements, for the following reasons. First, it was important to establish that the SBP remained increased in all cats to verify the diagnosis of systemic hypertension. This is most important in cats that do not have ocular pathology but are suspected of being hypertensive. In addition, retinal hemorrhage and detachments can be caused by other diseases in cats, so true hypertension must be differentiated from spurious increases in blood pressure caused by the stress of handling (ie, white coat effe~t ).~.,~ Second, during the treatment portion of the study it was critical to document whether once-daily AML controlled SBP for 24 hours in each cat. A blinded, placebo-controlled clinical trial was designed for the following reasons. Most investigators report a good correlation between direct and indirect blood pressure measurements in dogs and cats. 1~11.21-z3 However, others believe that indirect blood pressure measurements do not reflect true blood pressure because increases in blood pressure can occur when animals are handled or Some believe that systemic hypertension is overdiagnosed.2 Another concern is the reported decrease in some blood pressure measurements when the recordings are repeated over time; this

Amlodipine Clinical Trial 161 Table 3. Mean? standard deviation (range) of serum blood urea nitrogen concentration ([BUN]) and serum creatinine concentration ([Cr]) in 5 cats receiving amlodipine (AML) (0.625 mg) for 1 week (group 1) and 6 cats receiving AML (0.625 mg or 1.25 mg) for 16 weeks (group 2). No significant differences were observed. Group 1 (n = 5) Group 2 (n = 6) Day 0 Day 7 Day 0 Week 16 [BUN] (mg/dl) 39 2 22 (22-73) 35 t 19 (17-66) 33 t 10.3 (22-50) 32 2 7.1 (25-44) [Crl (mg/dl) 2.2 2 1.6 (1.1-4.9) 2.2 f 1.8 (1.0-5.4) 1.7 2 0.4 (1.2-2.5) 2.0 t 0.6 (1.2-2.6) Body weight (kg) 4.5 2 0.8 (3.6-5.4) 4.5 2 0.9 (3.5-5.7) 5.1 2 1.6 (3.4-7.0) 5.6 f 2.2 (3.5-8.8) is attributed to a training effect (ie, acclimation of the animal to the procedure).2h In dogs, this effect has been reported with both diastolic blood pressure and SBI?24 Zh In humans, SBP decreases over time and is associated with a decline in catecholamine excretion.*' These concerns were addressed in part in the present study by having a control group that did not receive the test drug, AML. If a decline in SBP had been observed in both AML and PLA groups on day 7, a training effect could have contributed to the decrease in pressure. Likewise, both groups were managed in a similar fashion except for treatment so a decline in SBP in the treated group would suggest there had been a treatment effect rather than just a reduction in stress or handling. Direct blood pressure measurements were not performed in the present study because the cats were clientowned and awake and it would be difficult to maintain peripheral arterial catheters for 24 hours in awake cats. Although considered unlikely, the possibility of a training effect cannot be excluded as the cause of the continued lower SBP at week 16, because no cat received PLA longer than 1 week. However, the time between the testing periods (day 7 to week 16) was 15 weeks, making a training effect unlikely. Additionally, there does not appear to have been any clinically significant decline in SBP from day 7 to week 16 (Table 1). Most investigators using indirect blood pressure measurements report averaging a number of individual readings to obtain an average value.' I' *' Comparisons of oscillometric methods of blood pressure measurement to direct blood pressure measurement have shown that averaging sequential blood pressure measurements (rather than relying upon single measurements) improves the reliability of the indirect readingzx In the current study, the use of an averaged value was considered acceptable because the mean coefficients of variation were less than 4%. Three cats failed to respond to 0.625 mg AML once daily and required a higher dose of AML (1.25 mg sid); all 3 cats weighed more than 5 kg. The body weight of cats did not change significantly after 7 days and 16 weeks of treatment with AML. This is consistent with the reports in humans and the report in cats that body weight is unaffected by AML administration.x l4 However, 1 cat gained 1.8 kg during the study. No cat developed clinical signs referable to hypotension. The lowest SBP recorded during the trial was 109 mm Hg in a cat weighing 3.6 kg. Hypotension is an uncommon adverse effect in humans receiving AML and was not reported in a retrospective study of hypertensive cats given AML."29 With the exception of inappetance and weight loss in the azotemic cat that was euthanized, no other adverse effects were reported by the owners. Three animals were euthanized before the completion of the study. The cat euthanized by the referring veterinarian for presumptive progression of renal disease had the highest [Cr] on day 0 (4.9 mg/dl); no necropsy was performed. Although the average [Cr] and [BUN] did not increase significantly during the study, 1 cat with initial isosthenuria had an increase in [Cr] during week 16 (day 0: 1.4 mg/dl; week 16: 2.6 mg/dl). Unfortunately, renal histopathology was not performed before or during the trial in this cat. The increase in [Cr] in this cat may be related to natural progression of chronic renal disease rather than AML. In humans, AML did not show any detrimental effect on renal hemodynamics or function.'x.20 In a recent clinical trial of AML in cats, [BUN] and [Cr] did not change when cats were given AML.h A weakness of the study is the lack of uniform followup 1 week after beginning the higher dose (1.25 mg sid) of AML in 3 cats. Although reevaluations were requested, the clients of the cats declined because this would require additional hospitalization in rapid succession to the previous visits. Each client did return their cat for periodic evaluations of SBP after the higher dose was begun; however, serial blood pressure measurements were not obtained as outlined by the protocol until week 16. For this reason, day 7 and week 16 data were not compared. Therefore, it is impossible to determine if an additional decline in SBP occurred from day 7 to week 16. Because of the varied eating habits of cats and the small sample size of the study, no attempt was made to coordinate feeding with drug administration or to alter the eating habits of the cats during the trial."' A report in humans showed that bioavailability of AML was not affected by food." Acknowledgments I appreciate the assistance of Dr Deena Sadek, Dr Forrest Hayes, Dr Andrew Hopkins, and Ms Prudence Walker. This study was funded by a Clinical Research Grant from the University of Florida, College of Veterinary Medicine. References I. Morgan RV. Systemic hypertension in four cats: Ocular and medical findings. J Am Anim Hosp Assoc 1986;22:615-621. 2. Littman MP. Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 1994;8:79-86. 3. Sansom J, Barnett KC, Dunn KA, et al. Ocular disease associated with hypertension in 16 cats. J Small Anim Pract 1994;35:604-611. 4. Henik RA. Diagnosis and treatment of systemic hypertension. Compend Contin Educ 1997;19:163-178. 5. Lesser M, Fox PR, Bond BR. Assessment of hypertension in 40

162 Snyder cats with left ventricular hypertrophy by Doppler shift sphygmomanometry. J Small Anim Pract 1992;33:55-58. 6. Henik RA, Snyder PS, Volk LM. Treatment of systemic hypertension in cats with amlodipine besylate. J Am Anim Hosp Assoc 1997;33:226-234. 7. Turner JL, Brogdon JD, Lees GE, Greco DS. Idiopathic hypertension in a cat with secondary hypertensive retinopathy associated with a high-salt diet. J Am Anim Hosp Assoc 1990;26:647-651. 8. Dukes J. Hypertension: A review of the mechanisms, manifestations and management. J Small Anim Pract 1992;33:119-129. 9. Kobayashi DL, Peterson ME, Graves TK, et al. Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 1990;4:58-62. 10. Binns SH, Sisson DD, Buoscio DA, et al. Doppler ultrasonographic, oscillometric sphygmomanometric, and photoplethysmographic techniques for noninvasive blood pressure measurement in anesthetized cats. J Vet Intern Med 1995;9:405-414. I I. Grandy JL, Dunlop CI, Hodgson DS, et al. Evaluation of the Doppler ultrasonic method of measuring systolic arterial blood pressure in cats. Am J Vet Res 1992;53:1166-1169. 12. Aristizabal D, Frolich DE. Calcium antagonists. In: Singh BN, Dzau VJ, Vanhouette PM, eds. Cardiovascular Pharmacology and Therapeutics. New York, NY: Churchill Livingstone; 1994: 185-202. 13. Frick MH, McGibney D, Tyler HM, et al. Amlodipine: A double blind evaluation of the dose response relationship in mild and moderate hypertension. J Cardiovasc Pharmacol 1988; 12(Suppl 7): S76-S78. 14. Mroczek WJ, Burris JF, Allenby KS. A double blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1988;12(Suppl 7):S79-S84. 15. Beresford AP, McGibney D, Humphrey MJ, et al. Metabolism and kinetics of amlodipine in man. Xenobiotica 1988;18:245-254. 16. Snyder PS. Evaluation of the antihypertensive agent amlodipine besylate in normotensive cats and in a cat with systemic hypertension. Proc. 12th Vet. Med. Forum 1994:978 (abstract). 17. Beresford AP, Macrae PV, Stopher DA. Metabolism of amlodipine in the rat and the dog: A species difference. Xenobiotica 1987; 18: 169-182. 18. Laher MS, Kelly JG, Doyle GD, et al. Pharmacokinetics of amlodipine in renal impairment. J Cardiovasc Pharmacol 1988; 12(Suppl 7):S60-S63. 19. Faulkner JK, McGibney D, Chasseaud LE et al. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br J Clin Pharmacol 1986;22:21-25. 20. Licata G, Scaglione R, Ganguazza A, et al. Effects of amlodipine on renal hemodynamics in mild to moderate hypertensive patients. Eur J Clin Pharmacol 1993;45:307-31 l. 21. Freundlich JJ, Detweiler DK, Hance HE. Indirect blood pressure determinations by the ultrasonic Doppler technique in dogs. Curr Ther Res 1972;14:73-80. 22. Garner HE, Hahn AW, Hartley JW, et al. Indirect blood pressure measurement in the dog. Lab Anim Sci 1975;25:197-202. 23. Weiser MG, Spangler WL, Gribble DH. Blood pressure measurements in the dog. J Am Vet Med Assoc 1977;171:364-368. 24. Kallet AJ, Cowgill LD, Kass PH. Comparison of blood pressure measurements obtained by dogs by use of indirect oscillometry in a veterinary clinic versus at home. J Am Vet Med Assoc 1997;210:651-654. 25. Bovee KC, Garg TN. A comparison of indirect blood pressure measurements to direct continuous telemetry in normal dogs. Proc. 14th Vet. Med. Forum 1996:473 (abstract). 26. Remillard RL, Ross JN, Eddy JB. Variance of indirect blood pressure measurements and prevalence of hypertension in clinically normal dogs. Am J Vet Res 1991;52:561-565. 27. Hossman V, Fitzgerald GA, Dollery CT. Influence of hospitalization and placebo therapy on blood pressure and sympathetic function in essential hypertension. Hypertension 1981;3: 1 13-1 18. 28. Meurs KM, Miller MW, Slater MR. Comparison of the indirect oscillometric and direct arterial methods for blood pressure measurements in anesthetized dogs. J Am Anim Hosp Assoc 1996;32:471-475. 29. Haria M, Wagstaff AJ. Amlodipine: A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs 1995;50:560-586. 30. Hand MS, Armstrong PJ. Nutritional requirements and feeding recommendations. In: Sherding RG, ed. The Cat: Diseases and Management. New York, NY: Churchill Livingstone; 1989: 117-140. 3 I. Faulkner JK, Hayden ML, Chasseaud LF, Taylor T. Absorption of amlodipine unaffected by food: Solid dose equivalent to solution dose. Arzneimittelforschung 1989;39:799-80 1.