Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure.
BACKGROUND
The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.


RESULTS
DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.


CONCLUSIONS
The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.
Kim
S
S
Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. kims@med.osaka-cu.ac.jp
Yoshiyama
M
M
Izumi
Y
Y
Kawano
H
H
Kimoto
M
M
Zhan
Y
Y
Iwao
H
H
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001552:Benzazepines / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000652:urine; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004452:Echocardiography; D019332:Endothelin-1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006334:Heart Function Tests / Q000187:drug effects*; D006909:Hydroxyproline / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D011945:Receptors, Angiotensin / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D015996:Survival Rate; D013777:Tetrazoles / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D002395:Catecholamines; D019332:Endothelin-1; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D000068756:Valsartan; D003094:Collagen; D018995:Myosin Heavy Chains; D014633:Valine; D006909:Hydroxyproline; C044946:benazepril