Bradykinin improves left ventricular diastolic function under long-term angiotensin-converting enzyme inhibition in heart failure.
Both systolic and diastolic cardiac dysfunction coexist in various degrees in the majority of patients with heart failure. Although ACE inhibitors are useful in the treatment of heart failure, the roles of bradykinin in the systolic and diastolic properties of left ventricular function under long-term treatment of ACE inhibitor have not been fully elucidated. We therefore evaluated the changes in left ventricular function, histomorphometry, and the expression of several failing heart related genes, by use of an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg per day), with an ACE inhibitor, enalapril (1 mg/kg per day), in dogs with tachycardia-induced heart failure (270 ppm, 22 days) and compared the effects to enalapril alone. Although there were no differences observed in blood pressure, left ventricular dimension, and percentage of fractional shortening, FR173657 significantly increased left ventricular filling pressure (P<0.01), prolonged the time constant of relaxation (P<0.05), and suppressed the expression of endothelial NO synthase and sarcoplasmic reticulum Ca(2+)-ATPase mRNA (P<0.05). FR173657 also upregulated collagen type I and III mRNA (P<0.05) and increased the total amount of cardiac collagen deposits (P<0.05) in left ventricle compared with that in the enalapril-treated group. In conclusion, endogenous bradykinin contributes to the cardioprotective effect of ACE inhibitor, improving left ventricular diastolic dysfunction rather than systolic dysfunction, via modification of NO release and Ca(2+) handling and suppression of collagen accumulation.
Fujii
Masanori
M
First Department of Internal Medicine, Central Research Laboratory, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan.
Wada
Atsuyuki
A
Tsutamoto
Takayoshi
T
Ohnishi
Masato
M
Isono
Takahiro
T
Kinoshita
Masahiko
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000627:therapeutic use*; D065168:Bradykinin Receptor Antagonists; D000252:Calcium-Transporting ATPases / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004656:Enalapril / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D011804:Quinolines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D024042:Collagen Type I; D024061:Collagen Type III; C105311:FR 173657; D011804:Quinolines; D012333:RNA, Messenger; D004656:Enalapril; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D001920:Bradykinin