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Angiotensin II receptor antagonists for heart failure
  1. Department of Clinical Pharmacology and Therapeutics,
  2. Ninewells Hospital and Medical School,
  3. Dundee DD1 9SY, UK

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ACE inhibitors have revolutionised the treatment of chronic heart failure; however, as is often the case with drug treatment, we are remarkably ignorant of exactly how they work. Understanding the mechanisms involved is of fundamental importance because it is a major goal of pharmacological research to produce more specific drugs that act on the mechanism producing clinical benefit while having no effect on the mechanisms producing adverse effects. This ideal scenario seems to be a possibility if we substitute angiotensin II receptor antagonist drugs for ACE inhibitors. The rather optimistic idea behind this is that most if not all of the benefits of ACE inhibitors are because of angiotensin II suppression while the main adverse effect of ACE inhibitors (cough) is caused by bradykinin accumulation. How has practice lived up to this theory?


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Basic pharmacological considerations

Angiotensin II exerts its effects by stimulating cell membrane receptors—AT1 and AT2 receptors. Virtually all of the recognised effects of angiotensin II are mediated by AT1 receptors, which are blocked by AT1receptor antagonists. However, these drugs leave the AT2receptor unblocked and it is a concern that AT2 receptors may be overstimulated by endogenous angiotensin II when AT1receptor antagonists are prescribed. However, it seems that AT2 receptor stimulation in the presence of an AT1 receptor antagonist may be beneficial, as AT2 receptors appear to mediate antiproliferative effects and may even attenuate the proliferative effects of AT1receptor stimulation.1 Clinical trials with AT1 receptor antagonists have not uncovered any nasty surprises that could be attributed to AT2 receptor stimulation. Clearly, if AT2 receptor stimulation is beneficial, …

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