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

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.