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OBJECTIVES Bradykinin exerts cardioprotective effects through bradykinin type-2 receptors (BK-2Rs). After acute myocardial infarction in rat, the heart adapts by increasing its number of BK-2Rs. However, in human chronic end-stage heart failure, the number of BK-2Rs is significantly decreased. Thus, the presence of a cardioprotective BK-2R signaling system may be critical in the prevention of pressure overload-induced heart failure. DESIGN To explain differences in myocardial BK-2R expression during cardiac overload, we studied: (1). spontaneously hypertensive rats (SHRs) of different ages, and (2). normotensive Sprague-Dawley rats subjected to aortic banding or angiotensin II infusion. METHODS AND RESULTS The mRNA levels of BK-2Rs were found to be significantly (P < 0.05) increased in the aging (12 and 20-month-old) SHRs (2.9- and 3-fold, respectively). Similarly, in the Sprague-Dawley rats, the expression of BK-2Rs was increased at 12 h (1.8-fold, P < 0.05) and at 3 days (3.1-fold, P < 0.05) after aortic banding, and at 2 weeks (2.2-fold) after angiotensin II infusion. In the 12-month-old SHRs, with compensated left ventricular hypertrophy (no fibrosis or left ventricular dysfunction), the amount of BK-2Rs was also significantly increased (1.8-fold, P < 0.05). However, in the 20-month-old SHRs, with a dramatic increase in fibrosis and development of diastolic dysfunction and heart failure, the amount of BK-2Rs were significantly decreased (63%, P < 0.05) specifically in the cardiac endothelial cells. CONCLUSIONS The present results show that, during pressure overload and compensated left ventricular hypertrophy, the expression of BK-2Rs is increased. However, ongoing pressure overload leads to a loss of BK-2Rs with a dramatic increase in left ventricular fibrosis followed by diastolic dysfunction and heart failure.

In experimental animals, kinins protect the myocardium from ischemia-reperfusion injuries and reduce left ventricular hypertrophy and progression of heart failure. This suggests that in humans, also, the presence of an intact kinin system is critical for the prevention of heart failure. In addition to the kinin-generating system, the concentration of kinins, and consequently the extent of their actions, is regulated by their degradation. In the vascular bed of the human heart, bradykinin (BK) is degraded by angiotensin-converting enzyme (ACE). In contrast, in the interstitium of the human heart, BK is degraded by neutral endopeptidase (NEP). For potentiating the beneficial effects of BK, one strategy is elevation of the BK concentration by inhibition of BK-degrading enzymes. An even more effective form of pharmacological control of BK elevation than inhibition of ACE alone might be the combined inhibition of ACE and NEP.

Background —Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue. Methods and Results —Cardiac membranes were prepared from the left ventricles of normal (n=5) and failing (n=10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M–like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal. Conclusions —The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart.

In experimental animals, bradykinin type-1 receptors (BK-1Rs) are induced during inflammation and ischemia, and, by exerting either cardioprotective or cardiotoxic effects, they may contribute to the pathogenesis of heart failure. Nothing is known about the expression of BK-1Rs in human heart failure. Human heart tissue was obtained from excised hearts of patients undergoing cardiac transplantation ( n = 13), due to idiopathic dilated cardiomyopathy (IDC; n = 7) or to coronary heart disease (CHD; n = 6), and from normal hearts ( n = 6). The expression of BK-1Rs was analyzed by means of competitive RT-PCR, Western blot analysis, and immunohistochemistry. Expression of BK-1R mRNA was increased in both IDC (2.8-fold) and CHD (2.1-fold) hearts compared with normal hearts. The observed changes were verified at the protein level. Expression of BK-1Rs in failing hearts localized to the endothelium of intramyocardial coronary vessels and correlated with an increased expression of TNF-α in the vessel wall. Treatment of human coronary artery endothelial cells with TNF-α increases their BK-1R expression. These novel results show that BK-1Rs are induced in the endothelium of intramyocardial coronary vessels in failing human hearts and so may participate in the pathogenesis of heart failure.

Because bradykinin (BK) appears to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of BK-degrading enzymes should potentiate such actions. The purpose of this study was to find out which enzymes are responsible for the degradation of BK in human plasma. Human plasma from healthy donors ( n = 10) was incubated with BK in the presence or absence of specific enzyme inhibitors. At high (micromolar) concentrations, BK was mostly (>90%) degraded by carboxypeptidase N (CPN)-like activity. In contrast, at low (nanomolar) substrate concentrations, at which the velocity of the catalytic reaction is equivalent to that under physiological conditions, BK was mostly (>90%) converted into an inactive metabolite, BK-(1–7), by angiotensin-converting enzyme (ACE). BK-(1–7) was further converted by ACE into BK-(1–5), with accumulation of this active peptide. A minor fraction (

OBJECTIVES We sought to study the expression of bradykinin type-2 receptors (BK-2Rs) in patients with heart failure (HF). BACKGROUND Recent work in experimental animals has suggested that bradykinin (BK) exerts cardioprotective effects through specific BK-2Rs. However, nothing is known about the regulation of BK-2R expression in the pathogenesis of human HF. METHODS Human heart tissue was obtained from excised hearts of patients undergoing cardiac transplantation (n = 13) and from normal hearts (n = 6) unsuitable for donation. The patients had HF due to idiopathic dilated cardiomyopathy (IDC) (n = 7) or coronary heart disease (CHD) (n = 6). Tissue samples from the left ventricles were analyzed by competitive reverse-transcriptase-polymerase chain reaction and Western blotting for the expression of BK-2R messenger ribonucleic acid (mRNA) and protein. RESULTS In both the IDC and CHD hearts, the level of BK-2R mRNA expression was found to be significantly lower (30% and 38% of control values, respectively) than that in normal hearts. Correspondingly, the BK-2R protein level was significantly reduced in both the IDC and CHD hearts (45% and 62% of control values, respectively) and apparently involved all myocardial cell types. The down-regulation of BK-2R expression in failing hearts did not correlate with decreased cellularity or with the expression pattern of other members of the G-protein-coupled receptor superfamily. However, BK-2R down-regulation in the failing hearts was associated with a decrease in endothelial nitric oxide synthase in both IDC (53% of control value) and CHD (43% of control value) hearts. CONCLUSIONS These results are the first to suggest that a loss of BK-2Rs is involved in the pathogenesis of human HF. (C) 2002 by the American College of Cardiology Foundation.