Reviews for Primary Care - Fall 2007 - (Page 35) The Renin-Angiotensin System and Cardiovascular Diseases Renin inhibitor Angiotensinogen Ang I Renin ACE inhibitors ACE Ang II Compensatory feedback ARBs AT1 receptor Harmful effects Aldosterone Figure 2. Mechanisms by which the compensatory rise in renin stimulated by angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics leads to increased generation of angiotensin II. Figure shows that inhibition of the production or action of angiotensin II by ACE inhibitors or ARBs, respectively, prevents stimulation of the AT1-receptor and disrupts the negative feedback loop through which angiotensin II normally inhibits renin release by the kidney. ACE inhibitors and ARBs thus stimulate a compensatory increase in renin release from the kidney, which ultimately leads to increased levels of angiotensin I and angiotensin II. A renin inhibitor would inhibit the reactive rise in renin activity that occurs with ACE inhibitors and ARBs and thus prevent increases in angiotensin I and angiotensin II levels. Ang, angiotensin; AT1, angiotensin II type I. www.medreviews.com which angiotensin II normally inhibits renin release, so that these drugs actually stimulate the release of renin from the kidney and activate the RAS (Figure 2).32 Does this stimulatory effect on the RAS matter? Clinical evidence suggests that it might. It was discovered often used for BP-lowering effects (valsartan 160 mg bid and candesartan 32 mg qd, respectively), which might also reflect the need to counteract the compensatory increase in renin activity. Thus there may be scope for improved organ protection with new therapies that might provide Patients with hypertension generate angiotensin II despite ACE inhibitor therapy. Studies have confirmed that this escape from ACE inhibition is associated with deteriorating control of blood pressure and poorer prognosis. more than 20 years ago that patients with hypertension generate angiotensin II despite ACE inhibitor therapy.33 Subsequent studies have confirmed that this escape from ACE inhibition was associated with deteriorating control of BP and poorer prognosis.34,35 The outcome benefits achieved with ARBs in patients with heart failure in Val-HeFT and CHARM required doses higher than those more comprehensive inhibition of the RAS. Does Increased RAS Suppression Improve Organ Protection? Is there any evidence that we can obtain superior organ protection by increasing RAS suppression beyond what we can achieve with standard doses of ACE inhibitors or ARBs? For ARBs, recent evidence indicates that increasing the dosage beyond current recommended levels in patients with diabetes leads to modest but significantly greater renoprotective effects,36 despite no further reduction in BP. These findings suggest that increased RAS suppression would be associated with improved organ protection independent of BP levels. Another approach to enhancing RAS suppression is to combine ACE inhibitor therapy and ARB therapy. Some clinical evidence indicates that this approach shows promise. The combination treatment of angiotensinII receptor blocker and angiotensinconverting-enzyme inhibitor in nondiabetic renal disease (COOPERATE) trial of 336 patients with non-diabetic renal disease demonstrated that combined treatment with trandolapril and losartan was significantly more effective at delaying the progression of kidney disease than was either drug alone (Figure 3).37 Evidence from other large outcome trials is rather more equivocal. Significant additional outcome benefits were seen in chronic heart failure patients in the CHARM-Added trial,38 but not in patients with acute heart failure following MI in VALIANT.15 Unfortunately, where these studies were in agreement was that ACE inhibitor and ARB combination therapy lacked the excellent tolerability of the monotherapies, with hyperkalemia emerging as a particular problem in these complex patients with advanced disease. In general, there is evidence that increasing RAS suppression beyond that achievable with currently approved doses of ACE inhibitor or ARB monotherapy can lead to improved clinical outcomes. But, although ACE inhibitors and ARBs have provided an excellent starting point for therapeutic inhibition of the RAS, we may need to look beyond these classes in order to optimize inhibition of this system. VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE 35 http://www.medreviews.com
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