Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Raasch
Walter
W
Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic of Schleswig-Holstein, Campus Lübeck, Germany. raasch@medinf.mu-luebeck.de
Jöhren
Olaf
O
Schwartz
Stefan
S
Gieselberg
Annabella
A
Dominiak
Peter
P
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000188:drug therapy*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009929:Organ Size; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D013777:Tetrazoles; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril; C077793:candesartan cilexetil