Inhibition of the renin-angiotensin system, with particular reference to dual blockade treatment.

Abstract

JRAAS 2001;2:146-52 Background The presence of diabetes profoundly increases the risk of developing cardiovascular disease, largely because of the adverse combination with hypertension. Hypertensive,diabetic patients carry a two-fold increase of developing cardiovascular complications compared with non-diabetics. Modulation of the renin-angiotensin system (RAS) has become essential in treating hypertension and delaying the onset of diabetic nephropathy. Since the 1980s, numerous studies have shown that the use of angiotensin-converting enzyme inhibitors (ACE-I) has beneficial effects when treating hypertension and renal disease in diabetes, as well as non-diabetic renal disease. Tight blood pressure (BP) control has become essential for this group of patients and the benefits are undisputed. The UKPDS study showed a 24% risk reduction among Type 2 diabetics in whom BP was reduced to below 150/85 mmHg over a study period of eight years. The HOT study showed significant risk reduction in cardiovascular events in diabetics in whom diastolic BP was reduced to approximately 80 mmHg (mean BP 144/81 mmHg). A remarkable proportion of this particular patient group was treated with an ACE-I. ACE inhibition alone is not always able to provide a satisfactory treatment strategy for the individual patient. Either insufficient BP control or continued microalbuminuria may prevail in spite of high doses of ACE-I; this has created interest in alternative ways of inhibiting the RAS. There are several reasons for optimising RAS blockade. During long-term ACE--I treatment, the phenomenon of ‘ACE-escape’ develops. It seems that plasma levels of angiotensin II (Ang II) and aldosterone may return to pre-treatment levels, which may induce incessant progression of nephropathy and chronic heart failure. In chronic heart failure patients, the angiotensin AT1-receptor blocker (ARB), valsartan, was added to the maximum recommended dose of ACE-I (40 mg of long-acting ACE-I) and significantly reduced the BP response to infused Ang II, even though the high-dose ACE-I had been given for over three months. This could be due to the fact that ACE-I do not completely block the conversion of angiotensin I (Ang I) to Ang II. Alternative pathways of converting Ang I to Ang II are of great influence, especially in the failing heart, kidneys and large resistance vessels. The chymase, cathepsin and serine protease–inhibitable conversion of Ang I to Ang II appear to be activated in disorders in which high levels of oxidative stress are present, such as vascular pro-inflammatory processes, atherogenesis and diabetes. In these circumstances, up to 60–70% of circulating Ang II may be produced by alternative pathways. Finally, tissue ACE activity, which is found in lung, blood vessels, myocardium and in the kidneys, has been proposed to mediate more long-term tissue effects, such as glomerular hypertrophy and left ventricular remodelling. This is of utmost importance, since tissue ACE activity is not always sufficiently blocked by regular doses of ACE-I, and also because the ‘ACE-escape’ mechanism returns plasma levels of Ang II to normal, so that tissue-ACE activity becomes uncontrolled at the level of the AT1 and AT2 receptors. 21