- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01444833
Changes After Angiotensin Converting Enzyme (ACE) Inhibitor Replacement by Angiotensin II Receptor Type I (AT1) Blocker (ADIRAS)
Molecular - Genetic Alterations in Adipose Tissue After Change in Therapy From ACE Inhibitors to AT1 Receptor Blockers in Patients With Essential Hypertension
Study Overview
Detailed Description
Arterial hypertension is nowadays considered a metabolic disease, due to its occurrence together with other risk factors of atherosclerosis like obesity, dyslipidemia, insulin resistance, impaired glucose regulation to diabetes mellitus type 2. These factors often result into the metabolic syndrome. Its pathogenetic mechanisms are not completely clarified yet, polygenic inheritance and environmental factors are probably involved. Therefore, from pathophysiological perspective of hypertension therapy a complex approach to the patient is needed. This approach requires the understanding of all known risk factors leading to the pharmacological and non-pharmacological intervention aimed to eliminate the risk factors of atherosclerosis. One of the main homeostatic systems participating in blood pressure regulation is the RAS.
The present pharmacotherapy provides the possibility to influence the RAS through the inhibition of a) renin, b)ACE or c) through blockade of AT1 receptors.
- Renin inhibitors belong to the recent therapeutic approaches in hypertension treatment. Clinical studies, which could enable their use in daily practice, have not been completed yet.
Inhibition of angiotensin converting enzyme prevents the transformation of angiotensin I (Ang I) to angiotensin II (Ang II), prevents the breakdown of vasodilatatory kinins, mainly bradykinin, leading to the NO-mediated vasodilatation. The positive effects of therapy with ACE inhibitors are based besides the decrease of circulating Ang II also on decreased influence of tissue Ang II, mainly in the vascular wall and on diminished norepinephrine release from neural terminals of autonomic nervous system (Noshiro et al. 1991). The ACE inhibitors reduce plasma Ang II levels, thus the AT1 and AT2 receptors are less stimulated by the hormone leading to upregulation of the homologue ACE2, thereby increasing the production of angiotensin (1-7) (Ferrario et al. 2005). Angiotensin (1-7) binds to the AT1 as well as to the AT2 receptors and to its tentative AT(1-7) receptor.
Some ACE inhibitors have a positive effect on improvement of glucose metabolism. The mechanism of improvement of insulin sensitivity has not been completely explained yet. It is supposed, that the positive insulin-sensitizing effects of ACE inhibitors could be mediated by hemodynamic changes - by improvement of skeletal muscle blood flow and/or by stimulation of insulin signaling pathways or by increasing the expression and the number of glucose transporter GLUT4. The improvement of insulin sensitivity during the therapy with ACE inhibitors correlated with the changes in the ion calcium/magnesium balance. The sympatholytic effect of the therapy with RAS inhibitors could also positively influence the metabolic parameters, supported by a study showing a decrease in serum epinephrine and an increase of insulin stimulated glucose uptake in normotensive volunteers treated with ACE inhibitor. In animal models of hypertension, the ACE inhibitors had a positive effect on reduction of free fatty acids levels and therefore a positive effect on insulin action.
- AT1 receptor blockade (by sartans) results in elevated plasma Ang II concentrations and to preferential stimulation of AT2 receptors. Compared to AT1, stimulation of AT2 receptors exerts an antagonistic effect by inducing vasodilatation, apoptosis, and by inhibiting growth and proliferation of vascular smooth muscle cells. In addition, high Ang II concentrations seem to upregulate low levels or even re-express missing AT2 receptors in adult rat adipose tissue. ACE2 expression is also upregulated under AT1 blockade thus increased concentrations of angiotensin (1-7) in vivo in humans are assumed even not studied yet. Angiotensin (1-7) binds preferentially to non-blocked AT2 receptors evoking additional depressor activity via kinin/NO/cGMP cascade inducing vasodilatation and improvement in hemodynamics.
Overall, ACE inhibition exerts its beneficial effects on blood pressure via decreased Ang II concentrations and elevated bradykinin. On the other hand, blockade of AT1 receptors causes simultaneous overstimulation of AT2 receptors by elevated concentrations of Ang II, angiotensin (1-7) and angiotensin A having a positive effect on adipogenesis resulting in changes of regulatory mechanisms influencing the insulin action.
The sartans have an insulin-sensitizing effect; their exact mechanism is unknown so far. Some of the AT1 receptor blockers display a weak peroxisome proliferator activator receptor (PPARγ) agonist activity which might promote the adipocyte differentiation. However, sartans without the PPARγ-agonist activity have a significant effect on adipocyte downsizing and improvement of insulin sensitivity markers as well. These results suggest that there may be a distinct mechanism, other than direct activation of PPARγ that is responsible for adipocyte differentiation and improvement of metabolic parameters.
It is supposed that adipose tissue, except from systemic hemodynamic and sympatholytic effect is responsible for the insulin-sensitizing effect of sartans. In the last 20 years, the adipose tissue has been well studied, since it is no more considered only an energy storage but also a source of several substances - hormones, enzymes and bioactive peptides generally called adipokines.
Human and rat adipose tissue contains complete local renin-angiotensin system (RAS). Components of adipose RAS undergo significant changes when the amount of adipose tissue and the adipocyte size enlarge. This leads to the assumption, that RAS plays an important role in regulation of adipose tissue mass. In vitro studies showed that Ang II inhibits adipocyte differentiation resulting in increased proportion of large insulin-resistant adipocytes and ectopic lipid deposition in other tissues. In the large adipocytes, expression and production of TNF is increased and adiponectin secretion inhibited through AT1 receptors. TNF is a cytokine impairing insulin action, highly expressed in adipose tissue in obesity and metabolic syndrome. It is known that the insulin sensitivity of adipocytes decreases with their size. RAS blockade stimulates adipogenesis in adipose tissue, probably via stimulation of AT2 receptors resulting in increased number of small insulin-sensitive cells. Several authors have observed a decrease in adipocyte size in retroperitoneal and epididymal adipose tissue in line with improved insulin sensitivity after RAS blockade in rats. Blockade of AT1 receptors in co-culture of human preadipocytes and adipocytes leaded also to increased adipogenesis. It is assumed that in vivo blockade of RAS might result in increased proportion of small adipocytes due to adipogenesis with simultaneous decrease in number of large cells due to apoptosis. The increased proportion of smaller adipocytes is reflected in changes of expression and release of adipokines producing more adiponectin and less TNF. Indeed, blockade of RAS elevates serum concentrations of adiponectin in patients with essential hypertension. In rats, serum concentrations as well as mRNA expression of adiponectin and PPARγ in adipose tissue increased. PPARγ plays probably a role in mechanisms related to the effect of RAS inhibition on changes in adipose tissue amount and its insulin sensitivity. In vivo in human body, to our knowledge these changes in production of RAS components in relation to adiposity and cellularity of the adipose tissue, to adipokines secretion and to parameters of insulin sensitivity have not been studied yet.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Stefan Zorad, Dr.
- Phone Number: 250 00421 2 54772800
- Email: stefan.zorad@savba.sk
Study Contact Backup
- Name: Adrian Oksa, MD.
- Phone Number: 628 00421 2 59370
- Email: adrian.oksa@szu.sk
Study Locations
-
-
-
Bratislava, Slovakia, 833 06
- Recruiting
- Institute of Experimental Endocrinology, SAS
-
Contact:
- Stefan Zorad, Dr.
- Phone Number: 250 00421 2 54772800
- Email: stefan.zorad@savba.sk
-
Contact:
- Adela Penesova, MD.
- Phone Number: 260 00421 2 54772800
- Email: adela.penesova@savba.sk
-
Principal Investigator:
- Richard Imrich, MD.
-
Principal Investigator:
- Katarina Krskova, Dr.
-
Principal Investigator:
- Miroslav Vlcek, MD.
-
Sub-Investigator:
- Adrian Oksa, MD.
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- essential hypertension
- ACE inhibitors
Exclusion Criteria:
- diabetes mellitus
- endocrinopathies
- no smokers
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Systemic Insulin Sensitivity after Replacement of ACE Inhibitor by AT1 Blocker
Time Frame: 6 months
|
Oral glucose tolerance test (OGTT) will be used to determine systemic insulin sensitivity.
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adipocyte Diameter from Subcutaneous Adipose Tissue after Replacement ACE Inhibitor by AT1 Blocker
Time Frame: 6 months
|
The tissue obtai ned by biopsy will be digested by collagenase and the diameter of isolated adipocytes will be evaulated by light microscopy.
|
6 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Stefan Zorad, Dr., Institute of Experimental Endocrinology SAS
Publications and helpful links
General Publications
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- Walters PE, Gaspari TA, Widdop RE. Angiotensin-(1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats. Hypertension. 2005 May;45(5):960-6. doi: 10.1161/01.HYP.0000160325.59323.b8. Epub 2005 Mar 14.
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- Engeli S, Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, Teboul M, Massiera F, Sharma AM. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Int J Biochem Cell Biol. 2003 Jun;35(6):807-25. doi: 10.1016/s1357-2725(02)00311-4.
- Ernsberger P, Koletsky RJ. Metabolic actions of angiotensin receptor antagonists: PPAR-gamma agonist actions or a class effect? Curr Opin Pharmacol. 2007 Apr;7(2):140-5. doi: 10.1016/j.coph.2006.11.008. Epub 2007 Feb 15.
- Ferrario CM, Jessup J, Gallagher PE, Averill DB, Brosnihan KB, Ann Tallant E, Smith RD, Chappell MC. Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors. Kidney Int. 2005 Nov;68(5):2189-96. doi: 10.1111/j.1523-1755.2005.00675.x.
- Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N, Yoshida D, Shimamoto K. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension. 2003 Jul;42(1):76-81. doi: 10.1161/01.HYP.0000078490.59735.6E. Epub 2003 Jun 9.
- Goossens GH, Blaak EE, van Baak MA. Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Obes Rev. 2003 Feb;4(1):43-55. doi: 10.1046/j.1467-789x.2003.00091.x.
- Gorzelniak K, Engeli S, Janke J, Luft FC, Sharma AM. Hormonal regulation of the human adipose-tissue renin-angiotensin system: relationship to obesity and hypertension. J Hypertens. 2002 May;20(5):965-73. doi: 10.1097/00004872-200205000-00032.
- Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab. 2004 Feb;30(1):13-9. doi: 10.1016/s1262-3636(07)70084-8.
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- Havel PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes. 2004 Feb;53 Suppl 1:S143-51. doi: 10.2337/diabetes.53.2007.s143.
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- Iwai M, Chen R, Imura Y, Horiuchi M. TAK-536, a new AT1 receptor blocker, improves glucose intolerance and adipocyte differentiation. Am J Hypertens. 2007 May;20(5):579-86. doi: 10.1016/j.amjhyper.2006.12.010.
- Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM. Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes. 2002 Jun;51(6):1699-707. doi: 10.2337/diabetes.51.6.1699.
- Jankowski V, Vanholder R, van der Giet M, Tolle M, Karadogan S, Gobom J, Furkert J, Oksche A, Krause E, Tran TN, Tepel M, Schuchardt M, Schluter H, Wiedon A, Beyermann M, Bader M, Todiras M, Zidek W, Jankowski J. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):297-302. doi: 10.1161/01.ATV.0000253889.09765.5f. Epub 2006 Nov 30.
- Kaplan NM. Hypertension and diabetes. J Hum Hypertens. 2002 Mar;16 Suppl 1:S56-60. doi: 10.1038/sj.jhh.1001344.
- Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab. 1998 Nov;83(11):3925-9. doi: 10.1210/jcem.83.11.5276.
- Keidar S, Kaplan M, Gamliel-Lazarovich A. ACE2 of the heart: From angiotensin I to angiotensin (1-7). Cardiovasc Res. 2007 Feb 1;73(3):463-9. doi: 10.1016/j.cardiores.2006.09.006. Epub 2006 Sep 19.
- Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000 Mar;52(1):11-34.
- Kim S, Moustaid-Moussa N. Secretory, endocrine and autocrine/paracrine function of the adipocyte. J Nutr. 2000 Dec;130(12):3110S-3115S. doi: 10.1093/jn/130.12.3110S.
- Mori Y, Itoh Y, Tajima N. Angiotensin II receptor blockers downsize adipocytes in spontaneously type 2 diabetic rats with visceral fat obesity. Am J Hypertens. 2007 Apr;20(4):431-6. doi: 10.1016/j.amjhyper.2006.09.016.
- Noshiro T, Way D, McGrath BP. Effect of angiotensin-converting enzyme inhibition on renal norepinephrine spillover rate and baroreflex responses in conscious rabbits. Clin Exp Pharmacol Physiol. 1991 May;18(5):375-8. doi: 10.1111/j.1440-1681.1991.tb01467.x.
- Oksa A, Gajdos M, Fedelesova V, Spustova V, Dzurik R. Effects of angiotensin-converting enzyme inhibitors on glucose and lipid metabolism in essential hypertension. J Cardiovasc Pharmacol. 1994 Jan;23(1):79-86. doi: 10.1097/00005344-199401000-00010.
- Pinterova L, Krizanova O, Zorad S. Rat epididymal fat tissue express all components of the renin-angiotensin system. Gen Physiol Biophys. 2000 Sep;19(3):329-34.
- Pinterova L, Zelezna B, Fickova M, Macho L, Krizanova O, Jezova D, Zorad S. Elevated AT1 receptor protein but lower angiotensin II-binding in adipose tissue of rats with monosodium glutamate-induced obesity. Horm Metab Res. 2001 Dec;33(12):708-12. doi: 10.1055/s-2001-19132.
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Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ANTICIPATED)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- MinHealth
- 2007/27-SAV-02 (OTHER_GRANT: Slovak Ministry of Health)
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