Changes After Angiotensin Converting Enzyme (ACE) Inhibitor Replacement by Angiotensin II Receptor Type I (AT1) Blocker

Molecular - Genetic Alterations in Adipose Tissue After Change in Therapy From ACE Inhibitors to AT1 Receptor Blockers in Patients With Essential Hypertension

It is supposed that the significant metabolic effects (improvement of insulin sensitivity) of hypertension therapy with renin-angiotensin system (RAS) blockers in humans are mediated mainly via changes in abdominal adipose tissue. This project is aimed to confirm the hypothesis that increased concentrations of circulatory angiotensin II after angiotensin II receptor type I (AT1) blockade leads, via stimulation of angiotensin II receptor type II (AT2), to activation of adipogenesis and improvement of insulin sensitivity. Therefore, in hypertensive patients, the components of RAS and the parameters of insulin sensitivity on systemic (in plasma) and local (in adipose tissue and in its interstitial fluid) level will be studied. The main aim of the study is to identify the changes occurring in patient before and 6 months after the conversion of therapy from angiotensin converting enzyme (ACE) inhibitors to AT1 receptor blockers. Observed parameters will include gene expression of RAS components, parameters of insulin sensitivity, amount, and cellularity of adipose tissue obtained by biopsy, evaluation of direct production of cytokines and angiotensins into the interstitial fluid of fat tissue obtained by microdialysis and evaluation of the selected parameters in plasma.

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.

1. 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.

2. 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.

3. 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.

Inclusion Criteria:

• essential hypertension
• ACE inhibitors

Exclusion Criteria:

• diabetes mellitus
• endocrinopathies
• no smokers