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

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Abstract
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.18 These 2 phenomena can explain why, in the presence of persistent plasma ACE inhibition, an attenuation of the BP response to ACE inhibitors occurs 24 to 48 hours after last drug intake, with an even faster return of plasma Ang II level toward its initial level.18 This counterregulation contributes to the flat dose-response curve of BP measured at trough that has been reported for most RAS blockers tested in patients with essential hypertension.20 In many patients with CHF, incomplete RAS blockade21 may also contribute to deterioration of LV function and to a poor cardiac prognosis associated with persistence of neurohormonal activation despite maximally recommended doses of ACE inhibitors.