Incomplete Aceinhibition

By use of an ACE-inhibitor this cascade of tissue alterations and blood pressure elevation can be altered. ACE inhibitors improve survival in nephropathy and heart failure, but as an antihypertensive drug it is well known that blood pressure levels can rise to pre-treatment values after long term ACE-inhibitor treatment. This could be due to the phenomenon termed "ACE-Escape". This is a mechanism where levels of plasma Angiotensin II and aldosterone somehow return to pre-treatment levels despite continues treatment with an ACE-inhibitor. This is due to bypassing of the Angiotensin converting enzyme and conversion of Angiotensin I to Angiotensin II by alternative enzymatic pathways [5]. Non- ACE dependant conversions of Angiotensin I to Angiotensin II are enhanced, especially in the failing heart, in the kidneys and in large resistance vessels [6]. Both Chymase and Cathepsin and other enzymes are able to contribute to the conversion of Angiotensin I to Angiotensin II and are found activated in disorders where, high levels of oxidative stress are present such as vascular pro-inflammatory processes, atherogenesis and especially diabetes mellitus [7].

Up to 60-70 % of circulating Angiotensin II may be produced by alternative pathways [8].

Secondary high levels of tissue ACE-activity mediating local Angiotensin I conversion, found in the lung, the blood vessels, myocardium and in the kidneys [9], have also been proposed to mediate a more long-term tissue damage like glomerular hypertrophy and left ventricular remodeling [10;11].

This is essential, since tissue ACE activity is not always sufficiently blocked by regular doses of ACE-1 inhibitor, so even though circulating levels of Angiotensin II are reduced, incessant tissue damage is ongoing.

The Angiotensin II receptor blockers should block circulating Angiotensin II, but other loopholes in the blockade of the RAS-system might also influence these agents. By blocking the receptor, circulating levels of Angiotensin II will rise and obviously compete with the AT1 receptor blocker at the receptor site. This requires use of a long acting ARB agents, since otherwise the AT1 receptor is totally exposed in long intervals during the day [12-14].

Furthermore, we do not know very much about the harmful effects of activating the other subgroups of the Angiotensin II receptors. At present 4 subgroups of receptors are known AT 1-4.

The effects of subclass 3 and 4 are unknown and in adult tissues the AT2 receptors are present only at low levels, mainly in the uterus, the adrenal gland, the central nervous system, the heart (cardiomyocytes and fibroblasts), and the kidney. But the AT2 receptors seem to be re-expressed or up regulated in experimental cardiac hypertrophy, myocardial infarction, and wound healing [15-17]. In humans all the known clinical effects of Angiotensin II are mediated by the AT1 receptor, but since AT1 antagonists do not block the AT2 receptor, exaggerated stimulation of the AT2 receptor occurs. This receptor could play an important role in apoptosis and fibrosis in the glomerulus and the myocardium, and could mediate vasoconstriction and elevated aldosterone production despite, Angiotensin II receptor blocker treatment.

We do not have detailed information about these mechanisms at present, but the role of unopposed stimulation of AT2 receptor will have a major bearing on the question of whether combined therapy with an Angiotensin II receptor blocker and an ACE inhibitor will exert additive benefit [18].

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