SYNERGISTIC EFFECTS OF ACE-INHIBITION AND ANG-II ANTAGONISM ON BLOOD-PRESSURE, CARDIAC WEIGHT, AND RENIN IN SPONTANEOUSLY HYPERTENSIVE RATS

Background Blockade of type I angiotensin (Ang) II receptors combined with ACE inhibition may amplify the efficacy of the renin-angiotensin system blockade because ACE inhibitors do not completely and permanent ly suppress Ang II production. Methods and Results Enalapril or losart an (1, 3, 10, and 30 mg/kg) or their combination was administered for 2 to 4 weeks to spontaneously hypertensive rats. The combination of lo w doses of each agent induced greater reductions in blood pressure (BP ) and left ventricular weight/body weight (LVW/BW) ratio than monother apy with the same or higher doses. When approximately equipotent regim ens of enalapril, losartan, and their combination, as judged by BP fal l, were compared, there were similar increases in plasma and renal ren in and in plasma Ang-(1-7) and Ang I and similar reductions in plasma angiotensinogen. Enalapril alone reduced plasma Ang II levels, and los artan alone increased Ang II levels. The combination of enalapril with losartan prevented or reduced the increase in Ang II levels observed with losartan alone. Conclusions These findings show that the synergis tic interaction between the effects of low doses of enalapril and losa rtan on BP and LVW/BW ratio is due to more effective inhibition of the renin-angiotensin system by their combination than by either agent al one. When both drugs are given together, the ACE inhibitor-induced fal l in plasma Ang II results in modulation of the Ang II antagonist-indu ced reactive rise in Ang II, thereby lowering the plasma Ang II concen tration,which competes with the antagonist for the Ang II receptors.