Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure

Abstract

Abstract-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 (PϽ0.01), prolonged the time constant of relaxation (PϽ0.05), and suppressed the expression of endothelial NO synthase and sarcoplasmic reticulum Ca 2ϩ -ATPase mRNA (PϽ0.05). FR173657 also upregulated collagen type I and III mRNA (PϽ0.05) and increased the total amount of cardiac collagen deposits (PϽ0.05) 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 2ϩ handling and suppression of collagen accumulation. Key Words: angiotensin-converting enzyme Ⅲ bradykinin Ⅲ Ca 2ϩ -transponding ATPase Ⅲ diastole Ⅲ fibrosis Ⅲ heart failure Ⅲ ventricular function, left A ngiotensin-converting enzyme inhibitors (ACEIs) exert beneficial effects on cardiac contractile function and are useful in improving both the symptoms and survival rate of a broad spectrum of patients with congestive heart failure (CHF). 1 In addition to suppressing the formation of angiotensin (Ang) II, the agents also prevent the breakdown of the potent vasodilator bradykinin (BK), which exerts its vasodilative action through BK type 2 (B 2 ) receptors. 2 Cardiomyocytes and cardiac fibroblasts have the capacity to generate BK, and they express functional B 2 receptors. BK possesses not only vasodilative action but also inotropic and antiproliferative properties. 3 Indeed, an ACEI increased the left ventricular (LV) ejection fraction and reduced LV chamber dimension and mass, but these effects were attenuated in B 2 receptor knockout mice. 4 In the clinical setting, however, the majority of patients with what is currently called "systolic heart failure" also have diastolic dysfunction of various degrees. 5 Ang II affects diastolic LV function through the changed composition of the LV wall (ie, increased interstitial fibrosis or fibrous content) and by virtue of the altered activity of the myofibroblasts in CHF. Because BK also possesses antiproliferative propertie...

Contribution of Vascular NAD(P)H Oxidase to Endothelial Dysfunction in Heart Failure and the Therapeutic Effects of HMG-CoA Reductase Inhibitor

“…21 Real-time PCR was performed with a LightCycler (Roche Molecular Biochemicals, Mannheim, Germany) using a commercially available mix containing Taq DNA polymerase, SYBR-Green I, and deoxyribonucleoside triphosphates (FastStart DNA Master SYBR Green I kit; Roche). Canine glutaraldehyde-3-phosphate dehydrogenase (GAPDH) and eNOS specific primer pairs were synthesized according to the published data.…”

“…Canine glutaraldehyde-3-phosphate dehydrogenase (GAPDH) and eNOS specific primer pairs were synthesized according to the published data. 21 Putative canine PCR primers for Nox4, gp91phox, p47phox and p22phox genes were designed based on homology with the highly conserved regions of the coding sequence of the human genes (gene bank: AF254621, BC032720, AF330627, NM000101). The canine Nox4, gp91phox, p47phox and p22phox-specific primer pairs were as follows.…”

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

“…Third, it has been shown that ACE inhibitors exert a BK-mediated favorable effect on LV diastolic function. 18 Thus, one mechanism by which BK exerts its protective effect on myocardial contractile function may be related to its effects on LV diastolic function. In agreement with previous reports, 15,16 this study showed a rightward shift of LV diastolic pressure-diameter curve, with an unchanged LV chamber stiffness after 3 weeks of pacing in vehicle-treated dogs.…”

“…This result seems to be in the same line as recent reports showing that chronic treatment with quinapril enhanced eNOS protein expression through a BK-dependent mechanism in normal rats 23 and that chronic treatment with enalapril preserved eNOS mRNA level, which was attenuated by concomitant BK B2 receptor antagonist in the pacinginduced HF. 18 The preserved eNOS expression could maintain NO production. By limiting afterload increase and by inhibiting myocardial mitochondrial respiration, 17,24 NO may have attenuated myocardial O 2 consumption during rapid pacing.…”

“…By limiting afterload increase and by inhibiting myocardial mitochondrial respiration, 17,24 NO may have attenuated myocardial O 2 consumption during rapid pacing. By its effect on cardiac remodeling, 18 NO may have mediated the beneficial effect of BK on LVED functions and thereby preserved myocardial contraction.…”