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Year : 2006  |  Volume : 38  |  Issue : 5  |  Page : 372-373

Combined treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB): 'Beating a dead horse' or meaningful mechanism-guided therapy?

Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666Al-Ain, United Arab Emirates

Correspondence Address:
G A Petroianu
Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666Al-Ain
United Arab Emirates
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0253-7613.27714

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How to cite this article:
Petroianu G A. Combined treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB): 'Beating a dead horse' or meaningful mechanism-guided therapy?. Indian J Pharmacol 2006;38:372-3

How to cite this URL:
Petroianu G A. Combined treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB): 'Beating a dead horse' or meaningful mechanism-guided therapy?. Indian J Pharmacol [serial online] 2006 [cited 2023 Sep 23];38:372-3. Available from: https://www.ijp-online.com/text.asp?2006/38/5/372/27714

I read with great interest the recent editorial, by Gautam and Aditya, and the 'Letters to the Editor', by Tandon and Sharma, et al . dealing with the pros and cons of combining ACE inhibitors with ARBs.[1],[2],[3]

The involvement of the renin-angiotensin-system (RAS) in various pathologies is well recognised. The inhibition of either production of angiotensin-II via ACE inhibition or blockage of the deleterious angiotensin-II effects using ARB are well established therapeutic approaches. The therapy of hypertension is, in the majority of cases, a combination therapy and almost every possible drug combination has been employed. Azizi et al , in France, Bisognano and Horwitz in the US and Meyer in Germany were among the first to look at the possibility of combination therapy with ACE inhibitors and ARB.[4],[5],[6]

The mechanistic arguments put forth for adding an ARB to full dose ACE inhibition are the existence of non-ACE-dependent angiotensin-II production (thus insensitive to ACE inhibition) and the importance of bradykinin-related effects of ACE inhibitors. While this line of thinking is certainly valid, the arguments are not particularly strong. One might be tempted to see, in the combination of ACE inhibitors with ARB, a perfect example for a pharmacodynamic pleonasm. Finnengan and Gleason recently reviewed data concerning combined ACE inhibitor and ARB therapy for hypertension and concluded that while studies have shown statistically significant blood pressure reductions with the ACE inhibitors-ARB combination therapy, clinical significance is lacking.[7] This view is not universally accepted. Kuriyama states that the majority of pilot studies, investigating the renoprotective effect of ACE inhibitors plus ARB, revealed a better antiproteinuric effect of this combination than either of the monotherapies for patients with either diabetic or non-diabetic renal diseases.[8]

These results are in line with the results of the COOPERATE Study (combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease) which concluded that "combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy".[9]

Recently, evidence has emerged that not all sartans (ARB) are equal. Several reviews have pointed out that, at clinically relevant dosage, telmisartan (but not other sartans) acts as a partial gamma-PPAR agonist.[10],[11],[12] Losartan metabolites (and possibly metabolites of other sartans) are also active at the same receptor.[13]

The constellation of obesity, dyslipidaemia, hypertension and insulin resistance is very common and has been baptised metabolic syndrome. Hypertension is a major determinant of cardiovascular events in these patients and strict blood pressure control is a must. For the high-risk hypertensive patient, ACE inhibitors, in addition to lowering blood pressure, increase insulin sensitivity and confer renal and vascular protection.[14],[15] Different theories have been put forth to explain the ACE inhibitor mediated protection. However, none of them is entirely convincing.[16]

The clinical effects of ACE inhibitors have similarities with those of both fibrates and glitazones, known activators of the peroxisome proliferator activator receptor (PPAR) alpha- and gamma-, respectively. We hypothesised that the long-term advantages of ACE inhibitor use, beyond mere BP lowering, might be due to a PPAR mediated effect.

Recently, we have been able to show that captopril and moexipril can induce catalase activity in rat liver.[17],[18] To the extent to which catalase activation is a surrogate marker for PPAR activation, the results lend support to the assumption that ACE inhibitors are upregulating PPAR. Our results complement those reported by da Cunha et al that enalapril upregulated the expression of alpha- and gamma-PPAR mRNA in mice.[19]

Due to the well-known species differences (i.e. sensitivity to peroxisome proliferation in rodents versus relative refractoriness in humans), extrapolation of results obtained in rodents to humans is difficult and therefore, as always, the caveat that further work is required, is necessary.[20] Also, further studies will have to elucidate the question whether the described phenomenon is a class effect (all ACE inhibitors) or not and, if yes, to quantify and compare the ability of the different ACE inhibitors to upregulate this class of receptors.

The finding, however, that at least some ACE inhibitors upregulate PPAR expression provides a possible mechanistic rationale for combining ACE inhibitors (prils) with sartans acting as partial PPAR agonist at these receptors. Mixing (some) sartans with (some) prils might make sense, after all.

  References Top

1.Gautam CS, Aditya S. Irrational drug combinations: need to sensitize undergraduates. Indian J Pharmacol 2006;38:169-70.  Back to cited text no. 1    
2.Tandon VR. Is enalapril and losartan combination irrational? Indian J Pharmacol 2006;38:295-6.  Back to cited text no. 2    
3.Sharma KK, Sahaya K, Mediratta PK. Repply. Indian J Pharmacol 2006; 38:296.  Back to cited text no. 3    
4.Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D, Mιnard J. Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation 1995;92:825-34.  Back to cited text no. 4    
5.Bisognano JD, Horwitz LD. Combination therapy with an angiotensin converting enzyme inhibitor and an angiotensin-ll receptorantagonist for refractory essential hypertension. West J Med 1998;168:272-4.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Meyer GJ. Antihypertensive therapy using a combination of angiotensin 1 receptor inhibitors with angiotensin-converting enzyme inhibitors. Dtsch Med Wochenschr 1998;123:681.  Back to cited text no. 6  [PUBMED]  
7.Finnengan PM, Gleason BL. Combination ACE inhibitors and angiotensin-II receptor blockers for hypertension. Ann Pharmacother 2003;37:886-9.  Back to cited text no. 7    
8.Kuriyama S. A clinical evaluation on the combination therapy with ACE-I and ARB and with ARB and CCB in patients with progressive chronic renal diseases. Nippon Rinsho 2002;60:2014-9.  Back to cited text no. 8  [PUBMED]  
9.Nakao N, Yoshimura A, Morita H, Takeda M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet 2003;361:117-24.  Back to cited text no. 9    
10.Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists: Beyond the renin-angiotensin system. J Hypertens 2004;22:2253-61.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Kurtz TW. Treating the metabolic syndrome: Telmisartan as a PPAR-gamma activator. Acta Diabetol 2005;42:9-16.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Kintscher U, Unger T. Vascular protection in diabetes: A pharmacological view of angiotensin-II type 1 receptor blockers. Acta Diabetol 2005;42:26-32.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Schupp M, Lee LD, Frost N, Umbreen S, Schmidt B, Unger T, et al . Regulation of peroxisome proliferator-activated receptor gamma activity by losartan metabolites. Hypertension 2006;47:586-9.  Back to cited text no. 13    
14.Gerstein HC. Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE. Diabetes Metab Res Rev 2002;18:82-5.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Zanella MT, Kohlmann O Jr, Ribeiro AB. Treatment of obesity hypertension and diabetes syndrome. Hypertension 2001;38:705-8.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.McFarlane SI, Kumar A, Sowers JR. Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol 2003;91:30-7.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Petroianu G, Adeghate A, Hassan MY, Saleh A, Kossanovic M, Ponery AS. Intraperitoneal exposure to captopril but not to lisinopril activates the peroxisome proliferator activated receptor (PPAR). 8th World Conference on Clinical Pharmacology and Therapeutics, Brisbane, Australia (Abstract # PO 185). Clin Experiment Pharmacol Physiol 2004;31:100.  Back to cited text no. 17    
18.Adeghate E, Hasan MY, Ponery AS, Nurulain SM, Petroianu GA. Subchronic exposure to high-dose ACE inhibitor moexipril induces catalase activity in rat liver. Mol Cell Biochem 2005;280:159-63.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.da Cunha V, Tham DM, Martin-McNulty B, Deng G, Ho JJ, Wilson DW, et al. Enalapril attenuates angiotensin-II-induced atherosclerosis and vascular inflammation. Atherosclerosis 2005;178:9-17.  Back to cited text no. 19    
20.Akbiyik F, Ray D, Bozkaya H, Demirpence E. Ligand and species-dependent activation of PPARalpha. Cell Physiol Biochem 2004;14:269-76.  Back to cited text no. 20    

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