gms | German Medical Science

To check whether antihypertensive effects are additive or synergistic upon blockade of both AT1-receptors and ACE, SHR were treated with candesartan-cilexetil (CC: 0.1-30mg/kg/d), ramipril (R: 0.03-10mg/kg/d), mibefradil (M: 1-150mg/kg/d) or combinations thereof. Systolic blood pressure (SBP), left ventricular weight (LVW) and the cardiac activity/mRNA levels of ACE were determined.

SBP was dose-dependently decreased by CC (IC50 [mg/kg]: 2.47), R (1.97), M (4.41), CC/R (0.68), and CC/M (5.68), respectively. Thus, efficacy of CC/R is approximately 3-fold enhanced compared to adequate monotherapies. Combining CC with R increased SBP reduction rather synergistically than additively, since the dose-response curve is shifted 6.6-fold leftwards compared to a hypothetical one. This was calculated by summing up the doses and corresponding effects, respectively of the R and CC monotreatment regimes. Derived from dose-response curves a total threshold dose <5.14 mg/kg was determined to exert synergistic effects when CC is combined with R. As shown for CC and R, these findings indicate that combining ACE inhibitors with AT1-antagonists does not gain synergistic effects when applied in full doses and that the clinical benefit will be the low-dose regime yielding in less side effects. Antihypertensive effects of M can not be enlarged when combined with CC. When LVW is correlated with SBP reduction, regression lines of CC, R and their combination were congruent while that for M was significantly flatter and became steeper under CC co-therapy. This underlines the pathophysiological significance of the RAAS in cardiac hypertrophy. Cardiac ACE activity was greatly reduced by R independently of SBP reduction and dosage. With SBP-ineffective doses of R, cardiac ACE mRNA levels were doubled, indicating a positive feed-back mechanism. In contrast, increase in ACE mRNA was renormalized after applying SPB-effective R doses, suggesting a SBP dependent regulation in cardiac ACE expression.