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Diabetic nephropathy is the leading cause of chronic renal failure in westernized countries. The polymorphism in angiotensin-converting enzyme (ACE), which leads to higher than normal levels of this enzyme, is a predictor of nephropathy in patients with diabetes. As increasing the levels of ACE by approximately 50% in this polymorphism is only calculated to increase the levels of angiotensin II by5%, whereas the levels of bradykinin will decrease by 20%, bradykinin may be nephroprotective. In diabetic mice without bradykinin B2 receptors, the only parameter that is altered compared with the diabetic mouse, is that the nephropathy is worse. Thus, in diabetic mice without a bradykinin receptor (Bdrb2(-/-)Ins2(+/C96Y)), compared with diabetic mice (Bdrb2(+/+)/Ins2(+/C96Y)), there is a greater kidney weight, increased urinary albumin output, and glomeruli mesangial sclerosis. In addition to reducing the levels of angiotensin II, vasopeptidase inhibitors increase the level of bradykinin. A vasopeptidase inhibitor (AVE7688) has been shown to prevent nephropathy developing and to ameliorate it once it has developed in Zucker diabetic rats. The nephroprotective effects (reduced albumin secretion and reduced kidney damage) of AVE7688 in Zucker diabetic rats were partially prevented by the bradykinin B2 receptor antagonist icatibant. These data establish that stimulation of bradykinin B2 receptors is a target in diabetic nephropathy.

The natriuretic peptide (NP) system is a cardioprotective hormonal system that fails to meet its cardioprotective end point during the development of cardiovascular complications such as hypertension and heart failure. The use of NPs or orally-active drugs that enhance the function of the NP system, are being explored for the treatment of such disorders. Much of the recent research has focused on vasopeptidase inhibitors that can inhibit neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) and thereby augment NP signalling while attenuating the renin–angiotensin–aldosterone system. These drugs offer several beneficial effects over conventional ACE inhibitors but the vasoactive peptide bradykinin, which is partly responsible for their beneficial effects, leads to serious side effects such as angioedema. The hope that these compounds will replace conventional drugs is fading away but they might be useful in targeted refractory populations immune to conventional drugs. The trends from the rece...

Blockade of the renin-angiotensin-aldosterone cascade is now recognised as a very effective approach to treat hypertensive, heart failure and high cardiovascular risk patients and to retard the development of renal failure. The purpose of this review is to discuss the state of development of currently available drugs blocking the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II receptor antagonists, with a special emphasis on the results of the most recent trials conducted with AT(2) receptor antagonists in heart failure and Type 2 diabetes. In addition, the future perspectives of drugs with dual mechanisms of action, such as NEP/ACE inhibitors, also named vasopeptidase inhibitors, are presented.

A new class of agents termed vasopeptidase inhibitors (VPIs) have the potential to be the next major advance in the treatment of hypertension, congestive heart failure (CHF) and related cardiovascular diseases. VPIs are single molecular compounds that inhibit two distinct zinc metalloproteases: neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). Vasopeptidase inhibition attenuates the formation of angiotensin II while potentiating endogenous levels of atrial natriuretic peptide (ANP) and bradykinin (BK). The combined effect has proven to be highly efficacious for the treatment of hypertension and CHF in experimental animal models and recently in man. This review highlights recent advances and disclosures over the last three years in this field.