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    Mean ± SEM percentage attenuation of the systolic pressor response (ΔSBP) effected by IV injection of the dose of angiotensin I that induced an approximately 35 mm Hg increase in SBP during administration of lactose monohydrate (placebo) in 6 clinically normal anesthetized cats that had received once-daily administration of various doses of 3 ARBs (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or placebo for 8 days in a crossover study. At approximately 90 minutes after the eighth oral daily dose of benazepril (2.5 mg/cat; white circles), telmisartan (0.5, 1.0, or 3.0 mg/kg; black circles), irbesartan (6 or 10 mg/kg; black triangles), or losartan (2.5 mg/kg; white squares), each cat underwent a rapid pressor response test. The cats had previously been instrumented with arterial telemetric blood pressure–measuring catheters; for 20 to 60 seconds prior to and up to 280 seconds following the bolus injection of angiotensin I, real-time blood pressure measurements were recorded as a graphed tracing from which SBP at baseline and at peak pressor response were derived to calculate ΔSBP. For each cat, percentage attenuation of the systolic pressor response was calculated according to the following formula: ([ΔSBP during treatment with placebo – ΔSBP during treatment with the drug of interest]/ΔSBP during treatment with placebo) × 100%. The dashed line at 75% denotes the cutoff used to predict clinical efficacy in pressor response studies of healthy human volunteers. BEN = Benazepril. IRB = Irbesartan. LOS = Losartan. TEL = Telmisartan.

  • View in gallery

    Mean ± SEM ΔSBP (mm Hg) in response to 1,000 ng of angiotensin I/kg administered IV approximately 90 minutes or 24 hours following the eighth oral daily dose of placebo (PL; black squares), benazepril (2.5 mg/cat; white circles), or telmisartan (3 mg/kg; black circles) in the 6 clinically normal anesthetized cats in Figure 1. a–dMeans with different letters are significantly (P < 0.05) different. RPRT = Rapid pressor response test. See Figure 1 for remainder of key.

  • 1. Syme HM, Barber PJ, Markwell PJ, et al. Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation. J Am Vet Med Assoc 2002; 220: 17991804.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Kobayashi DL, Peterson ME, Graves TK, et al. Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 1990; 4: 5862.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Syme HM, Markwell PJ, Pfeiffer D, et al. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med 2006; 20: 528535.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. J Vet Intern Med 2012; 26: 275281.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. 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 1997; 58: 535540.

    • Search Google Scholar
    • Export Citation
  • 6. Mathur S, Brown CA, Dietrich UM, et al. Evaluation of a technique of inducing hypertensive renal insufficiency in cats. Am J Vet Res 2004; 65: 10061013.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Brown SA, Brown CA, Jacobs G, et al. Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet Res 2001; 62: 375383.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 1997; 127: 337345.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Lefebvre HP, Brown SA, Chetboul V, et al. Angiotensin-converting enzyme inhibitors in veterinary medicine. Curr Pharm Des 2007; 13: 13471361.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Watanabe T, Mishina M. Effects of benazepril hydrochloride in cats with experimentally induced or spontaneously occurring chronic renal failure. J Vet Med Sci 2007; 69: 10151023.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. King JN, Maurer M, Toutain PL. Pharmacokinetic/pharmacodynamic modelling of the disposition and effect of benazepril and benazeprilat in cats. J Vet Pharmacol Ther 2003; 26: 213224.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Littman MP. Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 1994; 8: 7986.

  • 13. Buchwalder-Csajka C, Buclin T, Brunner HR, et al. Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system. Br J Clin Pharmacol 1999; 48: 594604.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Coleman AE, Schmiedt CW, Jenkins TL, et al. Evaluation of a rapid pressor response test in healthy cats. Am J Vet Res 2013; 74: 13921399.

  • 15. Hawking F. A review of progress in the chemotherapy and control of filariasis since 1955. Bull World Health Organ 1962; 27: 555568.

    • Search Google Scholar
    • Export Citation
  • 16. Miller RH, Smeak DD, Lehmkuhl LB, et al. Radiotelemetry catheter implantation: surgical technique and results in cats. Contemp Top Lab Anim Sci 2000; 39: 3439.

    • Search Google Scholar
    • Export Citation
  • 17. Brown SA, Langford K, Tarver S. Effects of certain vasoactive agents on the long-term pattern of blood pressure, heart rate, and motor activity in cats. Am J Vet Res 1997; 58: 647652.

    • Search Google Scholar
    • Export Citation
  • 18. Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621636.

  • 19. Brown S, Elliott J, Francey T, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med 2013; 27: S27S43.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Christ DD, Wong PC, Wong YN, et al. The pharmacokinetics and pharmacodynamics of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) in the dog. J Pharmacol Exp Ther 1994; 268: 11991205.

    • Search Google Scholar
    • Export Citation
  • 21. Wienen W, Entzeroth M, van Meel JCA, et al. A review on telmisartan: a novel, long-acting angiotensin II–receptor antagonist. Cardiovasc Drug Rev 2000; 18: 127156.

    • Search Google Scholar
    • Export Citation
  • 22. Carlucci L, Song KH, Yun HI, et al. Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates. Pol J Vet Sci 2013; 16: 555561.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats

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  • 1 Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30605.
  • | 2 Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30605.
  • | 3 Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30605.
  • | 4 Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30605.
  • | 5 Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30605.

Abstract

OBJECTIVE To compare the attenuation of the angiotensin I–induced blood pressure response by once-daily oral administration of various doses of angiotensin receptor blockers (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or lactose monohydrate (placebo) for 8 days in clinically normal cats.

ANIMALS 6 healthy cats (approx 17 months old) with surgically implanted arterial telemetric blood pressure–measuring catheters.

PROCEDURES Cats were administered orally the placebo or each of the drug treatments (benazepril [2.5 mg/cat], irbesartan [6 and 10 mg/kg], telmisartan [0.5, 1, and 3 mg/kg], and losartan [2.5 mg/kg]) once daily for 8 days in a crossover study. Approximately 90 minutes after capsule administration on day 8, each cat was anesthetized and arterial blood pressure measurements were recorded before and after IV administration of each of 4 boluses of angiotensin I (20, 100, 500, and 1,000 ng/kg). This protocol was repeated 24 hours after benazepril treatment and telmisartan (3 mg/kg) treatment. Differences in the angiotensin I–induced change in systolic arterial blood pressure (ΔSBP) among treatments were determined.

RESULTS At 90 minutes after capsule administration, only losartan did not significantly reduce ΔSBP in response to the 3 higher angiotensin doses, compared with placebo. Among drug treatments, telmisartan (3 mg/kg dosage) attenuated ΔSBP to a significantly greater degree than benazepril and all other treatments. At 24 hours, telmisartan was more effective than benazepril (mean ± SEM ΔSBP, 15.7 ± 1.9 mm Hg vs 55.9 ± 12.42 mm Hg, respectively).

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that telmisartan administration may have advantages over benazepril administration for cats with renal or cardiovascular disease.

Abstract

OBJECTIVE To compare the attenuation of the angiotensin I–induced blood pressure response by once-daily oral administration of various doses of angiotensin receptor blockers (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or lactose monohydrate (placebo) for 8 days in clinically normal cats.

ANIMALS 6 healthy cats (approx 17 months old) with surgically implanted arterial telemetric blood pressure–measuring catheters.

PROCEDURES Cats were administered orally the placebo or each of the drug treatments (benazepril [2.5 mg/cat], irbesartan [6 and 10 mg/kg], telmisartan [0.5, 1, and 3 mg/kg], and losartan [2.5 mg/kg]) once daily for 8 days in a crossover study. Approximately 90 minutes after capsule administration on day 8, each cat was anesthetized and arterial blood pressure measurements were recorded before and after IV administration of each of 4 boluses of angiotensin I (20, 100, 500, and 1,000 ng/kg). This protocol was repeated 24 hours after benazepril treatment and telmisartan (3 mg/kg) treatment. Differences in the angiotensin I–induced change in systolic arterial blood pressure (ΔSBP) among treatments were determined.

RESULTS At 90 minutes after capsule administration, only losartan did not significantly reduce ΔSBP in response to the 3 higher angiotensin doses, compared with placebo. Among drug treatments, telmisartan (3 mg/kg dosage) attenuated ΔSBP to a significantly greater degree than benazepril and all other treatments. At 24 hours, telmisartan was more effective than benazepril (mean ± SEM ΔSBP, 15.7 ± 1.9 mm Hg vs 55.9 ± 12.42 mm Hg, respectively).

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that telmisartan administration may have advantages over benazepril administration for cats with renal or cardiovascular disease.

Systemic arterial hypertension is a common cause of morbidity in cats, particularly those with CKD.1,2 Systemic arterial hypertension leads to an accelerated decline of renal function and exacerbation of proteinuria, the latter being a negative prognostic indicator in cats with spontaneous CKD.3,4 The pathogenesis of systemic arterial hypertension in cats with CKD is likely complex and multifactorial. Although additional causes undoubtedly exist, hyperactivity of the RAAS has been identified in cats with naturally occurring CKD5 or experimentally induced renal insufficiency.6,7 Therefore, suppression of this system is a logical therapeutic target for cats with CKD and systemic arterial hypertension.

Several RAAS-modifying agents have been developed for use in people with hypertension. In addition to their blood pressure–lowering properties, these drugs also have renoprotective effects, largely credited to their ability to reduce glomerular hypertension and proteinuria.8,9 Of the RAAS-modifying drugs available, only ACE inhibitors have been well studied in cats.7,9–11 However, most clinical veterinary reports5,12 describe disappointing antihypertensive efficacy of these drugs in that species.

An alternative choice for RAAS blockade may be found through the use of ARBs, which selectively antagonize the AT1 receptor, the latter being responsible for mediating the pathological effects of angiotensin II on the cardiovascular and renal systems. Available information regarding the use of ARBs in cats is limited, but a recent abstracta suggests that they may have favorable effects on proteinuria, appetite, and survival time in cats with naturally occurring CKD.

Exogenous angiotensin I or II challenge during continuous blood pressure measurement (the rapid pressor response test) is a valid means for evaluating the degree of RAAS blockade provided by antagonists of this system and is the preferred test for preclinical studies of healthy human volunteers.13 Identification of the dose of angiotensin I or II that produces a 30 to 35 mm Hg increase in SBP in otherwise untreated individuals is useful to predict clinically efficacious dosages of RAAS-blocking agents, which are able to attenuate this response by at least 75%.13 The safety, feasibility, and repeatability of this test in healthy cats have been reported.14

The objective of the study reported here was to compare attenuation of the angiotensin I–induced blood pressure response by once-daily oral administration of various doses of 3 ARBs (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or lactose monohydrate (placebo) for 8 days in clinically normal cats. We hypothesized that the RAAS-modifying agents assessed would attenuate the pressor response to varying agent- and dose-dependent degrees and that these drugs would be well tolerated in this species.

Materials and Methods

Cats

Six adult sexually intact male purpose-bred domestic shorthair cats were used for this placebo-controlled, crossover, experimental study. The mean ± SEM body weight for cats was 4.33 ± 0.2 kg, and each was approximately 17 months of age. Approximately 10 months prior to inclusion in the study, these cats were inoculated with Brugia malayi as part of a project designed to induce microfilariasis.15 All cats included in the present study failed to become microfilaremic. Prior to inclusion in the study, the cats’ general health status was determined by the findings of physical examination, CBC, serum biochemical analysis, and urinalysis. All cats were vaccinated against common viral diseases and had negative results for FeLV antigen and antibodies against FIV. Cats were housed individually in cages, had access to water at all times, and were fed a commercially available adult feline ration ad libitum. Ambient temperature was maintained between 20° and 22°C, and the cats were exposed to a cycle of 12 hours of light and 12 hours of darkness. The Institutional Animal Care Committee of the University of Georgia approved all activities.

Study protocol

Two weeks prior to any drug administration, a pressure-sensing telemetry deviceb was surgically inserted into the right femoral artery of each cat, as previously described.16,17 In 1 cat, implant failure required repositioning of the device to the left femoral artery during a separate anesthetic event. Thereafter, each telemetry device remained in the same location in each cat for the duration of the study. Following a 2-week recovery period, cats were treated orally once daily at approximately 8 AM with 1 placebo capsulec for 8 days (treatment days 1 to 8). A veterinarian or trained veterinary technician observed the cats daily for abnormalities such as weakness, vomiting, or diarrhea and for any other signs suggestive of adverse treatment effects. Food consumption was determined and recorded daily, and body weight was determined and recorded on the mornings of treatment days 1 and 8.

On the morning of treatment day 7, approximately 4 hours following administration of placebo, a radiotelemetry receiver was attached to each animal's cage for measurement of blood pressure and heart rate in ambulatory, undisturbed cats. All measurements were obtained in continuous 15-second intervals every 60 seconds for 90 minutes. To allow for a period of acclimatization following placement of the receivers, the first 30 minutes of data were discarded; therefore, reported values for blood pressure and heart rate represent a mean of values obtained over the last 60 minutes of the recording period. Traffic within the housing room was not allowed at any point during the recording period to eliminate the effects of human contact.17 On treatment day 8, 90 minutes following administration of the placebo capsule, each cat was anesthetized for administration of the rapid pressor response test. Data from these placebo-treated cats have been previously reported.14

After an interval of 3 weeks, the process of once-daily oral administration was repeated for each of the following drugs and dosages in the following order, separated by a 1-week washout period: irbesartand (6 and 10 mg/kg), benazeprile (2.5 mg/cat), telmisartanf (0.5, 1, and 3 mg/kg), and losartang (2.5 mg/kg). A licensed pharmacist compounded all ARBs into capsule form to achieve precise delivery of the target dose each day. On the morning of treatment day 7, approximately 4 hours following administration of the drug capsule, a radiotelemetry receiver was attached to each animal's cage for measurement of blood pressure and heart rate in ambulatory, undisturbed cats. On treatment day 8, 90 minutes following administration of the drug capsule, each cat was anesthetized for administration of the rapid pressor response test.

The entire 8-day treatment period was again repeated for each of benazepril and telmisartan (3 mg/kg), with pressor response testing performed approximately 24 hours after capsule administration on treatment day 8 (ie, at the time of assumed trough activity for each drug). As described peviously, an intervening 1-week washout period was allowed between these treatment periods.

Angiotensin I rapid pressor response test

Methods for preparation of angiotensin and administration of the rapid pressor response test have been described.14 Briefly, each cat was premedicated with butorphanol tartrateh (0.2 mg/kg, IM), and propofoli was administered for induction (7 mg/kg, IV) and maintenance (0.3 mg/kg/min, IV) of a stable plane of anesthesia. Each cat was positioned in right lateral recumbency.

Each of 4 IV bolus injections of angiotensin I was administered over approximately 2 seconds and was followed immediately by 1 mL of saline (0.9% NaCl) solution. Angiotensin I doses were administered in an escalating manner (20, 100, 500, and 1,000 ng/kg). The successive angiotensin I bolus was not administered until blood pressure returned to a stable baseline value, determined by visual inspection of the graphed tracing of blood pressure, and a minimum 10-minute washout period between bolus injections was allowed. For 20 to 60 seconds prior to and up to 280 seconds following each bolus injection, continuous, real-time blood pressure measurements were recorded as a graphed tracing (pressor response curve), with time (seconds) and pressure (mm Hg) on the x- and y-axis, respectively.

Analysis of the pressor response

Four observers (TLJ, AEC, CWS, and SAB), without knowledge of cat, date, time, and angiotensin dose, independently evaluated each pressor response curve, recording SBP and DBP at baseline and at Tmax. From these values, maximum ΔSBP (or systolic pressor response [SBP at Tmax – SBP at baseline]), maximum ΔDBP (or diastolic pressor response [DBP at Tmax – DBP at baseline]), and rate of SBP increase (systolic pressor response/[Tmax – time of angiotensin I injection]) were calculated.14 For each cat, percentage attenuation of the systolic pressor response was calculated for the dose of angiotensin I that induced an approximately 30 to 35 mm Hg increase in SBP during the placebo treatment, according to the following formula: ([ΔSBP during treatment with placebo – ΔSBP during administration with the drug of interest]/ΔSBP during treatment with placebo) × 100%.

Statistical analysis

Analyses were performed with the aid of 2 commercial software packages.j,k Data were tested for normality by means of a Kolmogorov-Smirnov test. Repeated-measures ANOVA was used to test for differences in ΔSBP, ΔDBP, and rate of increase in SBP among treatment groups, angiotensin doses, and observers. Multiple comparisons were adjusted for by means of a Tukey test. No significant observer effect or significant observer interactions were found; thus, observer was dropped from the model. Repeated-measures ANOVA was also used to test for differences in heart rate and SBP between treatment groups in awake, unstimulated cats and differences in food consumption and body weight changes over the treatment period between treatment groups. The full model included a fixed factor of treatment and a random factor of cat. Multiple comparisons were adjusted for by means of a Tukey test. An unstructured covariance structure was used in all repeated-measures models. All hypothesis tests were 2-sided, and the significance level was α = 0.05. All results are reported as mean ± SEM.

Results

No abnormalities were identified on the basis of prestudy physical examination or laboratory findings for any cat. No adverse events were noted during any treatment period. Mean ± SEM 24-hour rates of drug administration were 0.60 ± 0.04 mg/kg for benazepril at a dosage of 2.5 mg/cat; 0.51 ± 0.013 mg/kg, 1.0 ± 0.043 mg/kg, and 3.1 ± 0.059 mg/kg for telmisartan at a dosage of 0.5, 1, and 3 mg/kg, every 24 hours, respectively; 5.8 ± 0.11 mg/kg and 9.6 ± 0.21 mg/kg for irbesartan at a dosage of 6 and 10 mg/kg, every 24 hours, respectively; and 2.5 ± 0.032 mg/kg for losartan at a dosage of 2.5 mg/kg, every 24 hours. Mean ± SEM daily food consumption (mass consumed [g] and mass consumed as a percentage of body weight) was lower during the treatment period for losartan, compared with the placebo administration period (56.6 ± 5.3 g vs 75.9 ± 4.2 g, respectively, and 1.3 ± 0.13% vs 1.8 ± 0.16%, respectively). No significant differences in group means for body weight change over each treatment period were identified among treatments.

In awake, unstimulated cats, treatment with telmisartan resulted in significant reductions in SBP (for all dosages) and DBP (for the dosage of 3 mg/kg, q 24 h) and increases in heart rate (for the dosages of 1 and 3 mg/kg, q 24 h), compared with the effect of placebo. In addition, for telmisartan (dosage of 3 mg/kg, q 24 h), SBP and heart rate were significantly lower and higher, respectively, than for all other tested drugs (Table 1).

Table 1—

Mean ± SEM SBP, DBP, and heart rate in 6 awake unstimulated clinically normal cats following 7 days of once-daily oral administration of various doses of 3 ARBs (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or lactose monohydrate (placebo).

  BenazeprilTelmisartanIrbesartanLosartan
VariablePlacebo(2.5 mg/cat)0.5 mg/kg1 mg/kg 3 mg/kg6 mg/kg 10 mg/kg(2.5 mg/kg)  
SBP (mm Hg)111.1 ± 3.8a106.3 ± 3.3a,b97.5 ± 3.8c,d98.0 ± 5.9b,c,d 88.9 ± 6.7d108.4 ± 6.8a,b,c 109.5 ± 4.5a,b102.3 ± 4.7a,b  
DBP (mm Hg)75.3 ± 2.4a74.1 ± 4.5a68.4 ± 4.7a,b65.3 ± 4.2a,b 58.5 ± 4.6b73.8 ± 5.3a 73.1 ± 3.1a,b72.3 ± 2.6a,b  
Heart rate (beats/min)154 ± 5a168 ± 4a171 ± 6a176 ± 6b 177 ± 5b169 ± 8a 169 ± 4a168 ± 8a  

Within a row, values with different superscript letters are significantly (P < 0.05) different.

The cats had previously been instrumented with arterial telemetric blood pressure–measuring catheters. In an 8-day crossover study, each cat was treated orally once daily with benazepril (2.5 mg/cats), telmisartan (0.5, 1.0, or 3.0 mg/kg), irbesartan (6 or 10 mg/kg), or losartan (2.5 mg/kg). For each treatment, at 4 to 6 hours after the seventh daily capsule administration, blood pressure measurements were obtained in continuous 15-second intervals every 60 seconds for 90 minutes. To allow for a period of acclimatization following placement of the receivers, the first 30 minutes of data were discarded; therefore, reported values represent a mean of values obtained over the last 60 minutes of the recording period. Traffic within the housing room was not allowed at any point during the recording period to eliminate the effects of human contact.

For each drug treatment and for all 6 cats, pressor response curves were successfully generated following administration of each of the 4 doses of angiotensin I. No complications were observed during the data collection periods. Data for cats given placebo have been previously reported.14 In anesthetized cats at 90 minutes after capsule administration, significant differences in ΔSBP, ΔDBP, and rate of SBP increase were evident among treatments in response to administration of ≥ 100 ng of angiotensin I/kg (Table 2). When cats were treated with losartan and administered ≥ 100 ng of angiotensin I/kg, there were no significant reductions in ΔSBP and ΔDBP, compared with the effects of placebo. However, when cats received each other oral drug treatment, administration of ≥ 100 ng of angiotensin I/kg resulted in significant reductions in ΔSBP and ΔDBP, compared with the effects of placebo. Following angiotensin I injections, all drug treatments resulted in significant reductions in rate of SBP increase, with the exception of losartan- and benazepril-treated cats in response to injection of 100 ng of angiotensin I/kg and losartan-treated cats in response to injection of ≥ 500 ng of angiotensin I/kg. Depending on the dose of angiotensin I administered, telmisartan (dosage of 3 mg/kg, q 24 h) attenuated the systolic pressor response by a significantly greater degree than all other tested drug treatments. When cats were treated with the 3 dosages of irbesartan and 2 lower dosages of telmisartan, the responses to all doses of angiotensin I were similar to those achieved after benazepril treatment. In all cats treated orally with telmisartan (dosage of 3 mg/kg, q 24 h), ΔSBP did not exceed 5 mm Hg in response to angiotensin I doses ≤ 500 ng/kg.

Table 2—

Mean ± SEM ΔSPB and ΔDBP and rate of SPB increase in response to escalating doses of exogenous angiotensin I administered IV beginning 90 minutes following the eighth daily oral dose of various doses of 3 ARBs, benazepril hydrochloride, or placebo in the 6 clinically normal cats in Table 1 during anesthesia.

  Angiotensin I dose (ng/kg)
VariableTreatment201005001,000
ΔSBP (mm Hg)Placebo8.8 ± 1.325.7 ± 5.2a69.4 ± 12.2a96.2 ± 13.2a
 BEN (2.5 mg/cat)3.6 ± 2.27.7 ± 2.4b,c15.0 ± 2.4b,c21.7 ± 3.7b,c
 TEL (0.5 mg/kg)2.0 ± 0.85.6 ± 0.9b,c14.4 ± 2.5b18.8 ± 4.6b,c
 TEL (1 mg/kg)1.3 ± 0.63.4 ± 0.8b9.7 ± 1.3b12.4 ± 1.4c
 TEL (3 mg/kg)0.25 ± 0.23.3 ± 0.9b3.3 ± 0.4c6.9 ± 1.1d
 IRB (6 mg/kg)5.5 ± 2.68.2 ± 1.1b,c20.8 ± 2.9b29.1 ± 5.6b
 IRB (10 mg/kg)2.8 ± 1.26.0 ± 2.2b,c22.6 ± 5.9b32.1 ± 8.6b
 LOS (2.5 mg/kg)6.1 ± 1.618.6 ± 3.8a,c55.8 ± 9.4a84.2 ± 12.1a
ΔDBP (mm Hg)Placebo7.7 ± 1.123.4 ± 4.7a58.1 ± 9.4a77.7 ± 9.7a
 BEN (2.5 mg/cat)2.7 ± 1.75.2 ± 1.8b,c10.0 ± 1.6b,c15.5 ± 2.5b,c
 TEL (0.5 mg/kg)1.6 ± 0.64.3 ± 0.8b11.9 ± 1.9b,c16.3 ± 3.7b,c
 TEL (1 mg/kg)0.9 ± 0.52.1 ± 0.5b6.7 ± 0.9b,c9.3 ± 1.0c
 TEL (3 mg/kg)0.4 ± 0.22.2 ± 0.6b2.9 ± 0.6c5.8 ± 1.4c
 IRB (6 mg/kg)3.2 ± 1.46.0 ± 0.9b,c16.0 ± 2.2b21.3 ± 3.4b
 IRB (10 mg/kg)2.1 ± 1.04.8 ± 1.8b17.9 ± 4.5b25.3 ± 7.1b
 LOS (2.5 mg/kg)6.2 ± 1.616.9 ± 3.2a,c48.8 ± 8.0a69.3 ± 8.6a
Rate of SBP increase (mm Hg/s)Placebo0.249 ± 0.0260.441 ± 0.051a0.708 ± 0.066a0.907 ± 0.091a
 BEN (2.5 mg/cat)0.100 ± 0.0670.226 ± 0.089a,b,c0.292 ± 0.052c,d0.448 ± 0.109c
 TEL (0.5 mg/kg)0.062 ± 0.0250.199 ± 0.036b,c0.428 ± 0.070b,c,d0.641 ± 0.119b,c
 TEL (1 mg/kg)0.025 ± 0.0090.060 ± 0.014c0.274 ± 0.056c,d0.406 ± 0.055c,d
 TEL (3 mg/kg)0.009 ± 0.00760.061 ± 0.019c0.101 ± 0.018d0.155 ± 0.025d
 IRB (6 mg/kg)0.063 ± 0.0160.199 ± 0.040b,c0.502 ± 0.061a,b,c0.516 ± 0.036c
 IRB (10 mg/kg)0.069 ± 0.0350.133 ± 0.053c0.397 ± 0.057c0.538 ± 0.076c
 LOS (2.5 mg/kg)0.184 ± 0.0260.382 ± 0.057a,b0.664 ± 0.094a,b0.841 ± 0.057a,b

Each of 4 IV bolus injections of angiotensin I was administered for approximately 2 seconds and was followed immediately by 1 mL of saline (0.9 %NaCl) solution. Angiotensin I doses were administered in an escalating fashion (20, 100, 500, and 1,000 ng/kg). The successive angiotensin I bolus was not administered until blood pressure returned to a stable baseline value, determined by visual inspection of the graphed tracing of blood pressure, and a minimum 10-minute washout period between bolus injections was allowed. For 20 to 60 seconds prior to and up to 280 seconds following each bolus injection, continuous, real-time blood pressure measurements were recorded as a graphed tracing (pressor response curve). Four observers independently analyzed the pressor response curves and recorded SBP and DBP at baseline and at peak pressor response (Tmax). From these values, maximum ΔSBP (or systolic pressor response [SBP at Tmax – SBP at baseline]); maximum ΔDBP (or diastolic pressor response [DBP at Tmax – DBP at baseline]); and rate of SBP increase (systolic pressor response/[Tmax – time at angiotensin I injection]) were calculated.

BEN = Benazepril hydrochloride. IRB = Irbesartan. LOS = Losartan. TEL = Telmisartan.

Within a column and variable, values with different superscript letters are significantly (P < 0.05) different.

See Table 1 for remainder of key.

For each tested drug treatment, percentage attenuation of the systolic pressor response, calculated for the dose of angiotensin I producing an approximately 30 to 35 mm Hg increase in SBP in otherwise untreated cats, was determined (Figure 1). Of the tested drugs, mean percentage attenuation exceeded 75% only when cats were treated with benazepril and all dosages of telmisartan. All 6 cats had > 75% attenuation of ΔSBP when treated orally with telmisartan at dosages of 1 and 3 mg/kg, every 24 hours.

Figure 1—
Figure 1—

Mean ± SEM percentage attenuation of the systolic pressor response (ΔSBP) effected by IV injection of the dose of angiotensin I that induced an approximately 35 mm Hg increase in SBP during administration of lactose monohydrate (placebo) in 6 clinically normal anesthetized cats that had received once-daily administration of various doses of 3 ARBs (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or placebo for 8 days in a crossover study. At approximately 90 minutes after the eighth oral daily dose of benazepril (2.5 mg/cat; white circles), telmisartan (0.5, 1.0, or 3.0 mg/kg; black circles), irbesartan (6 or 10 mg/kg; black triangles), or losartan (2.5 mg/kg; white squares), each cat underwent a rapid pressor response test. The cats had previously been instrumented with arterial telemetric blood pressure–measuring catheters; for 20 to 60 seconds prior to and up to 280 seconds following the bolus injection of angiotensin I, real-time blood pressure measurements were recorded as a graphed tracing from which SBP at baseline and at peak pressor response were derived to calculate ΔSBP. For each cat, percentage attenuation of the systolic pressor response was calculated according to the following formula: ([ΔSBP during treatment with placebo – ΔSBP during treatment with the drug of interest]/ΔSBP during treatment with placebo) × 100%. The dashed line at 75% denotes the cutoff used to predict clinical efficacy in pressor response studies of healthy human volunteers. BEN = Benazepril. IRB = Irbesartan. LOS = Losartan. TEL = Telmisartan.

Citation: American Journal of Veterinary Research 76, 9; 10.2460/ajvr.76.9.807

At approximately 24 hours after capsule administration (time of expected trough effect for telmisartan and benazepril), once-daily oral administration of 3 mg of telmisartan/kg more effectively attenuated ΔSBP than did once-daily oral administration of 2.5 mg of benazepril/kg in response to injection of angiotensin I at doses ≥ 500 ng/kg in anesthetized cats. When cats received 3 mg of telmisartan/kg every 24 hours and 2.5 mg of benazepril every 24 hours, ΔSBP was 15.65 ± 1.90 mm Hg and 55.90 ± 12.42 mm Hg, respectively in response to 500 ng of angiotensin I/kg (P < 0.001), and 20.77 ± 4.02 mm Hg and 82.3 ± 16.44 mm Hg, respectively, in response to 1,000 ng of angiotensin I/kg (P < 0.001). At 24 hours after capsule administration, percentage attenuation of ΔSBP for the dose of angiotensin I that induced an SBP increase of approximately 30 to 35 mm Hg in the otherwise untreated cats was 78.9 ± 5.5% and 31.16 ± 93% for telmisartan (dosage of 3 mg/kg, q 24 h) and benazepril (dosage of 2.5 mg/kg), respectively. At all tested doses of angiotensin I, treatment with 3 mg of telmisartan/kg every 24 hours resulted in a value of ΔSBP at 24 hours after capsule administration on treatment day 8 that was not significantly different from the value recorded at 90 minutes after capsule administration or that recorded for benazepril treatment at 90 minutes after capsule administration on treatment day 8 (Figure 2).

Figure 2—
Figure 2—

Mean ± SEM ΔSBP (mm Hg) in response to 1,000 ng of angiotensin I/kg administered IV approximately 90 minutes or 24 hours following the eighth oral daily dose of placebo (PL; black squares), benazepril (2.5 mg/cat; white circles), or telmisartan (3 mg/kg; black circles) in the 6 clinically normal anesthetized cats in Figure 1. a–dMeans with different letters are significantly (P < 0.05) different. RPRT = Rapid pressor response test. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 76, 9; 10.2460/ajvr.76.9.807

Discussion

At the dosages given to the cats of the present study, telmisartan more effectively blocked the systolic pressor response to exogenous angiotensin I than did benazepril, irbesartan, and losartan and had effects that outlasted those of benazepril, the only drug currently labeled in the United States for RAAS blockade in cats. In contrast, losartan had effects that were similar to placebo, whereas those of irbesartan were intermediate to those of telmisartan and losartan.

In human medicine, ARBs have become the fastest growing class of antihypertensive drugs available for prescription. Selectivity for the AT1 receptor subtype endows drugs of the ARB class a mechanistic advantage over ACE inhibitors, in that ARBs preserve the beneficial effects associated with stimulation of angiotensin II subtype-2 receptors. In addition, this specificity allows ARBs to antagonize the detrimental effects of angiotensin II independent of its source, thereby circumventing ACE-independent proteolytic pathways responsible for persistent angiotensin II production during treatment with ACE inhibitors, a phenomenon termed angiotensin breakthrough.18

Losartan, the first ARB with oral bioavailability, was approved for clinical use in people in 1995. In the United States, this drug has received the most attention from veterinary clinicians, with anecdotal reports of success in the treatment of proteinuric renal disease in dogs and recommended doses ranging from 0.125 to 1 mg/kg/d in that species.19 In the present study, losartan performed no better than placebo when given orally to cats at a dosage of 2.5 mg/kg/d. This finding is in keeping with the failure of 4 mg of losartan/kg administered orally to significantly reduce blood pressure in cats with experimentally induced hypertensive renal insufficiency.6 It is known that dogs form little (if any) of the active metabolite of losartan (ie, EXP 3174) when the drug is given orally at pharmacological doses.20 This metabolite is responsible for a large portion of the antihypertensive effects of the drug. It is not known whether cats are similarly incapable of forming EXP 3174; if so, this may explain the poor performance of losartan in the present study.

Telmisartan is an insurmountable (ie, causing a rightward shift of the angiotensin II concentrationresponse curve with a decrease in the maximal response), selective antagonist of the AT1 receptor that has high lipophilicity and an adverse effect profile in people that is similar to that of placebo.21 A veterinaryspecific formulation of telmisartanl has recently been licensed in Europe for the treatment of proteinuria in cats with CKD. An abstracta describing results of a single clinical trial on the effect of telmisartan on proteinuria, appetite, and survival time in 224 cats has suggested that telmisartan may be useful for the reduction of proteinuria and for improvement of quality of life in cats with CKD.

In all 6 cats of the present study, telmisartan was well tolerated, with no adverse drug effects identified. The effects of telmisartan also exceeded those of all other tested drugs, with minimal increases in systolic pressor response at 90 minutes after capsule administration. In fact, in all 6 cats treated orally with telmisartan at a dosage of 3 mg/kg, every 24 hours, the systolic pressor response was not > 11 mm Hg in response to any of the 4 angiotensin I doses administered. This finding is in stark contrast to the greatest response (138 mm Hg) when cats were treated orally with placebo.

In people, the terminal half-life of telmisartan is relatively long (20 to 24 hours), making it suitable for once-daily dosing,21 whereas in cats, the half-life of telmisartan is reportedly shorter (7.7 hours).m The results of the present study suggested that the angiotensin I-blocking effects of this drug were sustained through the 24-hour dosing period in cats, with a small, nonsignificant difference in ΔSBP at 90 minutes and at 24 hours after capsule administration in response to each of the angiotensin I doses administered. The opportunity for once-daily dosing provides this drug with an advantage over benazepril, for which there was significant loss of efficacy at 24 hours after capsule administration, translating into only 31.16 ± 93% attenuation of the systolic pressor response at this time point, compared with 78.9 ± 5.5% effected by telmisartan (dosage of 3 mg/kg, q 24 h).

The most important limitation to the present study resulted from likely differences in drug absorption following oral administration. For each drug or the placebo, we chose to evaluate the systolic pressor response in cats at 90 minutes after capsule administration. In cats, Tmax for telmisartan occurs 0.5 hours following an orally administered dose,p and minimum plasma ACE activity is detected approximately 1 hour following an orally administered dose of benazepril.9 Although similar data for losartan or irbesartan in this species are not available, data on dogs suggest that losartan's parent compound has a mean ± SEM Tmax of 0.86 ± 0.67 hours and irbesartan has a Tmax of 2.83 ± 0.31 hours to 5.52 ± 2.33 hours.22 Although testing cats at the 90-minute posttreatment time point was intended to approximate the time of peak effect of each drug, it is possible that differences in performance among these drugs may be attributed to differences in the timing of maximum drug effect.

We also chose to evaluate the various drugs and dosages in a fixed order, which may have introduced an unintended effect of time on the study findings. Sequential intraday doses of angiotensin I were separated by a minimum interval of 10 minutes, and a stable blood pressure tracing was required prior to administration of the subsequent dose. Furthermore, our group has evaluated the repeatability of the rapid pressor response test in the same 6 cats used in the present study and found no significant differences for any pressor response variable between replicate days.14 Replicate tests in that study14 were conducted on 2 days separated by an interval of several months, with the intervening days dedicated to collection of the present study data. Therefore, these repeatability data provide specific information regarding the repeatability of this test during the present study period.

The findings of the present study in cats have suggested that telmisartan, administered at a dosage of 3 mg/kg, every 24 hours over an 8-day period, likely provides more complete and sustained RAAS blockade than benazepril when administered at a dosage of 2.5 mg/kg, every 24 hours over a similar period. Moreover, telmisartan appeared to have the benefit of once-daily administration. This drug may prove useful in the treatment of cats with renal or cardiovascular disease. Further studies are warranted to evaluate the efficacy of telmisartan in the treatment of clinical patients.

At the dosage tested, losartan had effects on the systolic pressor response to exogenous angiotensin I that were equivalent to those of placebo, a finding that clinicians currently prescribing this drug should consider when treating cats with cardiovascular or renal disease. Finally, drugs of the ARB class were well tolerated in clinically normal cats at the dosages tested.

Acknowledgments

Supported in part by the Veterinary Medical Experiment Station of the University of Georgia College of Veterinary Medicine.

Presented in part as an oral presentation at the American College of Veterinary Internal Medicine Forum, Seattle, June 2013.

The authors thank Emily Garber, Lisa Reno, Lynn Reece, and Lauren Heidingsfelder for technical assistance.

ABBREVIATIONS

ACE

Angiotensin-converting enzyme

ARB

Angiotensin receptor blocker

AT

1 Angiotensin II, subtype-1

CKD

Chronic kidney disease

DBP

Diastolic arterial blood pressure

ΔDBP

Maximum change in diastolic arterial blood pressure

RAAS

Renin-angiotensin-aldosterone system

SBP

Systolic arterial blood pressure

ΔSBP

Maximum change in systolic arterial blood pressure

Tmax

Time of peak systolic pressor response

Footnotes

a.

Sent U, Goessl R, Lang I, et al. Efficacy of long-term treatment with telmisartan oral solution on quality of life and disease progression in cats with chronic kidney disease (abstr), in Proceedings. Int Soc Feline Med World Feline Vet Cong 2013;65.

b.

Model TA11 PA-C40, Data Sciences International, Saint Paul, Minn.

c.

Lactose monohydrate 250 mg, PCCA USA, Houston, Tex.

d.

Avapro, Bristol-Myers Squibb, New York, NY.

e.

Benazepril hydrochloride 5 mg, Solco Healthcare USA, Cranbury, NJ.

f.

Micardis, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Conn.

g.

Losartan potassium, Sandoz Inc, Princeton, NJ.

h.

Torbugesic injectable 10 mg/mL, Fort Dodge Animal Health, Fort Dodge, Iowa.

i.

Propoflo injectable 10 mg/mL, Abbott Laboratories, Abbott Park, Ill.

j.

SAS, version 9.2, SAS Institute Inc, Cary, NC.

k.

Prism, version 6, GraphPad Software Inc, La Jolla, Calif.

l.

Semintra, Boehringer Ingelheim Pharmaceuticals Inc, Ingelheim, Germany.

m.

Sent U, Lang I, Moore G. Characterization of telmisartan in cats (abstr), in Proceedings. Int Soc Feline Med World Feline Vet Cong 2013;66.

References

  • 1. Syme HM, Barber PJ, Markwell PJ, et al. Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation. J Am Vet Med Assoc 2002; 220: 17991804.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Kobayashi DL, Peterson ME, Graves TK, et al. Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 1990; 4: 5862.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Syme HM, Markwell PJ, Pfeiffer D, et al. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med 2006; 20: 528535.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. J Vet Intern Med 2012; 26: 275281.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. 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 1997; 58: 535540.

    • Search Google Scholar
    • Export Citation
  • 6. Mathur S, Brown CA, Dietrich UM, et al. Evaluation of a technique of inducing hypertensive renal insufficiency in cats. Am J Vet Res 2004; 65: 10061013.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Brown SA, Brown CA, Jacobs G, et al. Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet Res 2001; 62: 375383.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 1997; 127: 337345.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Lefebvre HP, Brown SA, Chetboul V, et al. Angiotensin-converting enzyme inhibitors in veterinary medicine. Curr Pharm Des 2007; 13: 13471361.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Watanabe T, Mishina M. Effects of benazepril hydrochloride in cats with experimentally induced or spontaneously occurring chronic renal failure. J Vet Med Sci 2007; 69: 10151023.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. King JN, Maurer M, Toutain PL. Pharmacokinetic/pharmacodynamic modelling of the disposition and effect of benazepril and benazeprilat in cats. J Vet Pharmacol Ther 2003; 26: 213224.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Littman MP. Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 1994; 8: 7986.

  • 13. Buchwalder-Csajka C, Buclin T, Brunner HR, et al. Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system. Br J Clin Pharmacol 1999; 48: 594604.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Coleman AE, Schmiedt CW, Jenkins TL, et al. Evaluation of a rapid pressor response test in healthy cats. Am J Vet Res 2013; 74: 13921399.

  • 15. Hawking F. A review of progress in the chemotherapy and control of filariasis since 1955. Bull World Health Organ 1962; 27: 555568.

    • Search Google Scholar
    • Export Citation
  • 16. Miller RH, Smeak DD, Lehmkuhl LB, et al. Radiotelemetry catheter implantation: surgical technique and results in cats. Contemp Top Lab Anim Sci 2000; 39: 3439.

    • Search Google Scholar
    • Export Citation
  • 17. Brown SA, Langford K, Tarver S. Effects of certain vasoactive agents on the long-term pattern of blood pressure, heart rate, and motor activity in cats. Am J Vet Res 1997; 58: 647652.

    • Search Google Scholar
    • Export Citation
  • 18. Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621636.

  • 19. Brown S, Elliott J, Francey T, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med 2013; 27: S27S43.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Christ DD, Wong PC, Wong YN, et al. The pharmacokinetics and pharmacodynamics of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) in the dog. J Pharmacol Exp Ther 1994; 268: 11991205.

    • Search Google Scholar
    • Export Citation
  • 21. Wienen W, Entzeroth M, van Meel JCA, et al. A review on telmisartan: a novel, long-acting angiotensin II–receptor antagonist. Cardiovasc Drug Rev 2000; 18: 127156.

    • Search Google Scholar
    • Export Citation
  • 22. Carlucci L, Song KH, Yun HI, et al. Pharmacokinetics and pharmacodynamics (PK/PD) of irbesartan in Beagle dogs after oral administration at two dose rates. Pol J Vet Sci 2013; 16: 555561.

    • Crossref
    • Search Google Scholar
    • Export Citation

Contributor Notes

Address correspondence to Dr. Coleman (mericksn@uga.edu).