To check whether antihypertensive effects are additive or synergistic upon blockade of both angiotensin (AT1)-receptors and angiotensin-converting enzyme (ACE), spontaneously hypertensive rats (SHR) were treated with candesartan–cilexetil (0.1–30 mg/kg per day), ramipril (0.03–10 mg/kg per day), the calcium-antagonist mibefradil (1–150 mg/kg per day) or combinations thereof. Systolic blood pressure (SBP), left ventricular weight (LVW) and the cardiac activity/mRNA levels of ACE were determined.
SBP was decreased by candesartan–cilexetil [inhibitory concentration (IC50) (mg/kg): 2.47], ramipril (1.97), mibefradil (4.41), candesartan–cilexetil/ramipril (0.68), and candesartan–cilexetil/mibefradil (5.68). Combining candesartan–cilexetil with ramipril increased SBP reduction synergistically rather than additively, since the dose–response curve was shifted 6.6-fold leftwards compared to a hypothetically generated additive curve, calculated by summing up the doses and corresponding effects of the ramipril and candesartan–cilexetil monotreatment regimes. A total threshold dose < 5.14 mg/kg (derived from dose–response curves) was found to exert synergistic effects when candesartan–cilexetil was combined with ramipril. Antihypertensive effects of mibefradil can not be increased when combined with candesartan–cilexetil. When LVW was correlated with SBP reduction, regression lines of candesartan–cilexetil, ramipril and their combination were congruent, while that for mibefradil was significantly flatter and became steeper under candesartan–cilexetil co-administration. Cardiac ACE activity was greatly reduced by ramipril independently of SBP reduction and dosage. With SBP-ineffective doses of ramipril, cardiac ACE mRNA levels were doubled, indicating a positive feedback mechanism. The increase in ACE mRNA was renormalized when SPB-effective ramipril doses were applied, suggesting a blood pressure-dependent regulation of cardiac ACE expression.
Since synergy was observed only after combining low doses of ramipril and candesartan–cilexetil, prospective clinical trials should be performed on a low-dose combination, revealing the antihypertensive/antiproliferative benefits.
Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic of Schleswig-Holstein, Campus Lübeck, Germany.
Sponsorship: AstraZeneca (Wedel, Germany) supported this study by supplying a grant.
Correspondence and requests for reprints to Walter Raasch Ph.D., Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Tel: +49 451 5002698; fax: +49 451 5003327; e-mail: email@example.com
Received 28 August 2003 Revised 13 October 2003 Accepted 28 October 2003See editorial commentary on page 459