Inhibition of the renin-angiotensin-aldosterone system in cats and dogs:
The emerging role of angiotensin II receptor blockers

Amanda Coleman, University of Georgia, Athens, GA, USA
Jonathan Elliott, Royal Veterinary College, London, UK

The renin-angiotensin-aldosterone system and an introduction to angiotensin receptor blockers

The renin-angiotensin-aldosterone system (RAAS) is important in the physiology of blood pressure regulation and in the adaptation of the kidney to the loss of functioning nephrons, as occurs in chronic kidney disease (CKD). Hyperfiltration driven by RAAS activation is a maladaptive mechanism that exacerbates proteinuria, the severity of which is linked to progressive loss of functioning nephrons and to poorer patient outcomes.1-3 In addition, the hyperfiltration and accompanying proteinuria of CKD may be exacerbated by systemic arterial hypertension (HT), which, in turn, may hasten the decline of renal function and aggravate glomerulosclerosis.4,5 Dysfunction of the RAAS is implicated in the pathophysiology of HT in many species.

In veterinary medicine, angiotensin-converting enzyme inhibitors (ACE-i) have been used since the 1980s to treat heart disease and since the early 2000s to manage proteinuria in CKD patients. While these drugs demonstrably decrease glomerular hypertension, systemic arterial blood pressure, and proteinuria, the concept of blocking the RAAS by reducing the formation of angiotensin II (and as a consequence, decreasing a major stimulus for excess aldosterone secretion) may be too simplistic. Indeed, the use of ACE-i as single agent to control HT has proven disappointing in both dogs and cats. In addition, despite their benefit in lowering proteinuria within populations, ACE-i are not universally successful, with degree of antiproteinuric effect varying considerably on a patient-to-patient basis. For example, in a clinical trial designed to evaluate the efficacy of enalapril as a treatment for naturally occurring proteinuria, a clinically significant (i.e., 50%) reduction in proteinuria was noted in only 9/14 (64%) subjects, with 3/14 (22%) experiencing an increase in proteinuria despite therapy with enalapril.6 However, there are relatively few published randomized controlled clinical trials examining the antiproteinuric effect of ACE-i in dogs with CKD, in which large enough group sizes and different dose rates have been examined to be sure of the true efficacy of this group of drugs.

Selective and tight-binding inhibition of the angiotensin II, subtype 1 (AT1) receptor is a relatively new approach to interfering with the RAAS system that may have some advantages over ACE inhibition. First, this approach preserves the potentially beneficial effects associated with stimulation of the angiotensin II, subtype 2 (AT2) receptor. Expression of the AT2 receptor appears to be upregulated in times of stress, and activation of these receptors seems to counter-balance the detrimental consequences of AT1 receptor activation by antiproliferative, vasodilatory, antifibrotic and natriuretic effects. In addition, AT2 receptor activation seems to restore endothelial cell function. Selective AT1 receptor inhibition leaves the AT2 receptors free to interact with angiotensin II, which may favorably rebalance angiotensin II's downstream effects in patients with kidney disease, heart failure, HT, or a combination of these. In addition, because the AT1 receptor mediates feedback inhibition of renin release, its blockade is associated with increased angiotensin II levels, which are available to interact with the unopposed AT2 receptors, potentially amplifying their beneficial effects. How much this rebalancing effect contributes to the antihypertensive action of an AT1 receptor blocker (ARB) is unclear, but AT2 receptor activation is likely to be at least somewhat beneficial.

Specificity for the AT1 receptor also allows ARBs to antagonize the detrimental effects of angiotensin II independent of the latter's source, circumventing ACE-independent proteolytic pathways that are known to contribute to angiotensin II production. The well-described phenomenon of aldosterone breakthrough is thought to be explained, at least in part, by upregulation, or lack of blockade, of non-ACE pathways, which lead to the continued formation of angiotensin II, restoring plasma aldosterone concentrations to pre-treatment levels. Aldosterone breakthrough has been documented in dogs with experimental RAAS activation7,8 and naturally occurring myxomatous mitral valve disease,9 all treated with ACE-i. In people, aldosterone breakthrough is a well-recognized phenomenon not only in patients treated with an ACE-i, but also in those receiving an ARB, suggesting that persistence of angiotensin II production (i.e., angiotensin II breakthrough) is only part of the 'story'.10 Recently, aldosterone breakthrough was documented in 2 of 5 healthy, telmisartan-treated dogs undergoing pharmacologic RAAS activation,11 and evaluation of this phenomenon's incidence in dogs treated with an ARB is an area of ongoing investigation. Aldosterone break through has been demonstrated to occur in human patients receiving ARBs to a similar extent as those receiving ACE-i. Nonetheless, focus on aldosterone as a marker of RAAS activation should not under estimate the multitude of additional, non-aldosterone-mediated, detrimental effects of AT1 receptor activation, which are mitigated during treatment with ARBs.

Finally, in addition to theoretical advantages over ACE-i, ARBs may also have advantages when compared to other antihypertensive agents. For example, differences between the effects on the renal microvasculature of these drugs as compared to the dihydropyridine calcium channel blocker, amlodipine, may translate to differences in these drugs' renoprotective effects. Amlodipine causes preferential dilation of the afferent renal arteriole, which may exacerbate glomerular hypertension and promote progressive renal injury, especially if systemic arterial blood pressure is not effectively decreased during its administration. In contrast, through preferential dilation of the efferent renal arteriole, RAAS-blocking agents (both ACE-i and ARB) reduce intraglomerular pressure, mitigating glomerular hypertension and proteinuria, if present. However, the clinical significance imparted by these theoretical differences is not known.

Angiotensin II, subtype 1 receptor blockers (ARBs) in veterinary medicine

Losartan, the first ARB with oral bioavailability, was approved for clinical use in people in 1995. Since, a total of nine ARB have completed clinical development, making this class the most rapidly-growing of the antihypertensives. Likely due to its relative affordability, compared to other available ARBs, losartan has received the most attention from veterinary clinicians, particularly in the USA, with anecdotal reports of success in the treatment of proteinuria in dogs.12 However, in preclinical studies of healthy cats13 and dogs,14 losartan was no better than placebo in attenuating the angiotensin I-induced rise in systolic arterial blood pressure (SBP) when administered at a dosage of 2.5 mg/kg q24h (i.e., 2.5 times the maximum anecdotally recommended dosage12). The failure of 4 mg of losartan/kg to reduce SBP significantly in cats with experimentally induced hypertensive renal insufficiency supports these findings.15 It is noteworthy that the dog forms little of the active metabolite of losartan (EXP 3174), which is largely responsible for the antihypertensive effects of the drug.16 While it is not known whether cats are similarly incapable of forming EXP 3174, this may explain the poor performance of losartan in these preclinical studies.

In the studies referenced above, the ARB telmisartan was found to attenuate the angiotensin I-induced rise in SBP more effectively than benazepril (in cats), enalapril (in dogs), losartan (in cats and dogs), irbesartan (in cats) and placebo, suggesting a potential advantage of this drug for the treatment of cardiovascular and renal diseases in these species.13,14 In a separate study, telmisartan treatment was associated with measurable reductions in indirectly measured SBP in awake, unstimulated cats.17 Results from these studies, among others, revealed the potential utility of telmisartan for RAAS blockade in dogs and cats. As such, to date, telmisartan is the ARB that has been evaluated with the greatest rigor in companion animals.

A veterinary specific formulation of telmisartan was first licensed in Europe in 2013 for the treatment of proteinuria in cats with CKD. In a prospective, randomized, investigator-blinded clinical trial of 224 cats with naturally occurring CKD, telmisartan (1 mg/kg PO once daily) was shown to be non-inferior to benazepril (0.5-1.0 mg/kg PO once daily) for the reduction of time-averaged urinary protein-to-creatinine ratio (UPC), when administered for 3-6 months.18 Anecdotal reports, including one published case detailing successful UPC reduction in a dog with renal proteinuria that was poorly responsive to relatively high doses of benazepril,19 suggest that the drug is likely to be useful in this species, as well. Additional studies, designed to evaluate the efficacy of telmisartan in naturally occurring canine proteinuric renal disease, are warranted.

Two recent, prospective, multicenter, double-blinded, placebo-controlled clinical trials - one conducted at 51 European centers,20 and the other carried out at 33 primary care facilities in the United States and Canada21 - have evaluated the antihypertensive efficacy and safety of telmisartan oral solution when administered to a combined total of 483 spontaneously hypertensive cats with SBP of 160-200 mmHg. In both studies, compared to placebo, treatment with telmisartan oral solution was associated with both a statistically significant and clinically relevant decrease in SBP relative to baseline. On average, telmisartan resulted in mean SBP decreases of 19-23 mmHg by day 14 of treatment, whereas mean SBP reductions of 7-9 mmHg were noted in placebo-treated cats over the same time period. The telmisartan-induced decrease in SBP was sustained throughout a 4- or 6-month dosing period in both studies, with mean SBP reductions of 28-31 mmHg documented at study end. These data support the efficacy of telmisartan for the treatment of feline systemic hypertension, although the utility of this drug in cats with SBP >200 mmHg, evidence of severe target organ damage, severe azotemia, or a combination of these, remains untested. Furthermore, the optimal SBP to protect the kidneys and how this is influenced by the level of proteinuria in the individual patient remains to be investigated in veterinary medicine.

Conclusions and future directions

Angiotensin receptor blockers offer several theoretical advantages over ACE-i when used for the treatment of patients with cardiovascular and renal diseases. Pre-clinical work in normal cats and dogs supports the superiority of these drugs (in particular, telmisartan) over ACE-i for more effective RAAS blockade, with the benefit of once-daily dosing. The incidence of aldosterone breakthrough in patients treated with ARB remains to be elucidated.

Clinical trials in cats with naturally occurring CKD and systemic arterial hypertension have demonstrated the safety and efficacy of telmisartan for proteinuria and SBP reduction, although the drug's performance in the setting of severe systemic hypertension (i.e., SBP >200 mmHg) and severe renal azotemia requires further study. Whether telmisartan can be used safely in combination with amlodipine to achieve lower target SBPs in cats, and if using it in this manner leads to enhanced renoprotection, remains to be determined. The use of telmisartan in dogs with similar conditions has not yet been examined in randomized controlled clinical trials, so the theoretical advantages of angiotensin receptor blockade over ACE inhibition remain to be examined. This question deserves careful attention, and several ongoing trials aim to address this need.

Finally, whether ARBs have utility for delaying the progression of CKD in cats and dogs, and for the treatment of other cardiovascular conditions, represent important questions that are in need of further investigation.

Author conflicts of interest:

Both authors have acted as paid consultants to Boehringer Ingelheim Ltd, the company that holds the product authorization for telmisartan as an antihypertensive agent for use in cats.

References:

1. Jacob F, Polzin DJ, Osborne CA, et al. Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure. J Am Vet Med Assoc 2005;226:393-400.

2. Brown SA, Finco DR, Brown CA, et al. Evaluation of the effects of inhibition of angiotensin converting enzyme with enalapril in dogs with induced chronic renal insufficiency. Am J Vet Res 2003;64:321-327.

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;20:528-535.

4. Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. J Vet Intern Med 2012;26:275-281.

5. Jepson RE, Elliott J, Brodbelt D, et al. Effect of control of systolic blood pressure on survival in cats with systemic hypertension. J Vet Intern Med 2007;21:402-409.

6. Grauer GF, Greco DS, Getzy DM, et al. Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 2000;14:526-533.

7. Lantis AC, Ames MK, Atkins CE, et al. Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs. J Vet Pharmacol Ther 2015;38:65-73.

8. Ames MK, Atkins CE, Lee S, et al. Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs. Am J Vet Res 2015;76:1041-1050.

9. Ames MK, Atkins CE, Eriksson A, et al. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. J Vet Cardiol 2017;19:218-227.

10. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007;3:486-492.

11. Konta M, Nagakawa M, Sakatani A, et al. Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs. J Vet Cardiol 2018;20:376-383.

12. Brown SE, J.; Francey, T.; Polzin, D.; Vaden, S. . Consensus Recommendations for Standard Therapy of Glomerular Disease in Dogs. J Vet Intern Med 2013;27:S27-S43.

13. Jenkins TL, Coleman AE, Schmiedt CW, et al. Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats. Am J Vet Res 2015;76:807-813.

14. Coleman AE SC, Handford CG, Reno LR, Garber ED, Brown SA. . Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers in normal dogs. (abstract) Journal of Veterinary Internal Medicine 2014;28:976-1134.

15. Mathur S, Brown CA, Dietrich UM, et al. Evaluation of a technique of inducing hypertensive renal insufficiency in cats. Am J Vet Res 2004;65:1006-1013.

16. 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;268:1199-1205.

17. Coleman AE, Brown SA, Stark M, et al. Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake, clinically normal cats. J Feline Med Surg 2018:1098612X18761439.

18. Sent U, Gossl R, Elliott J, et al. Comparison of Efficacy of Long-term Oral Treatment with Telmisartan and Benazepril in Cats with Chronic Kidney Disease. J Vet Intern Med 2015;29:1479-1487.

19. Bugbee AC, Coleman AE, Wang A, et al. Telmisartan treatment of refractory proteinuria in a dog. J Vet Intern Med 2014;28:1871-1874.

20. Glaus AM EJ, Albrect B. Efficacy of telmisartan in hypertensive cats: Results of a large European clinical trial. J Vet Intern Med 2018; Dec 18. doi: 10.1111/jvim.15394. [Epub ahead of print].

21. Coleman AE, Brown SA, Traas AM, et al. Efficacy of oral telmisartan for the treatment of systemic hypertension in cats (abstract) J Vet Intern Med 2018;32:2142.