Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists

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Abstract
Blockade of the renin-angiotensin system* (RAS) with ACE inhibitors or angiotensin II type 1 receptor (AT1R) antagonists has become one of the most successful therapeutic approaches in medicine. Within 25 years, substantial evidence has accumulated to indicate that this therapy reduces blood pressure (BP),1 left ventricular (LV) mass,2 and proteinuria.3 RAS blockade results in a decrease in cardiovascular morbidity and mortality in patients with chronic heart failure (CHF)4–6 or LV systolic dysfunction7 and after myocardial infarction (MI).8,9 RAS blockers retard the progression of renal insufficiency in type 1 (ACE inhibitors10) and type 2 (AT1R antagonists11,12) diabetes mellitus and nondiabetic chronic renal disease.13–15 Finally, a high dose of an ACE inhibitor administered in the evening reduces the rate of death, cardiac events, and stroke in patients with a high cardiovascular risk at baseline.16 Several mechanisms contribute to the beneficial effects of RAS blockers in cardiovascular and renal therapy, schematically the hemodynamic consequences of angiotensin II (Ang II) neutralization and the suppression of the Ang II–dependent generation of growth-promoting cytokines, free oxygen radicals, and fibrosis mediators in tissues.17 An ACE inhibitor administered at usual daily doses only suppresses plasma Ang II levels within a few hours after dose intake, and similarly, usual daily doses of an AT1R antagonist do not block AT1Rs over 24-hour periods.18,19 This has led to the concept of combined RAS blockade. The “escape” observed with single-site RAS blockers is due to the conjunction of the progressive clearance from the body of the drug at the end of the dosing interval and the counterregulatory reactive rise in plasma active renin that increases Ang I, the ACE substrate, or Ang II, the AT1R agonist, proportionally to the suppression of the Ang II negative feedback on renin release. …

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