Metabolism of Bradykinin by Peptidases in the Lung

Dragovic, T.; Igić, Rajko; Erdös, Ervin G.; Rabito, Sara F.

doi:10.1164/ajrccm/147.6_pt_1.1491

Cited by 38 publications

(13 citation statements)

References 36 publications

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“…The cells also contain two metallopeptidases. Because these peptidases are among the most active enzymes that cleave biologically important peptides and hormones, they can participate in peptide metabolism (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) by lung cells. The two zinc plasma membrane anchored metallopeptidases (carboxypeptidase M and neutral endopeptidase 24.11) had relatively lower activity in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane-bound and lysosomal peptidases in human alveolar macrophages.

Jackman¹,

Tan²,

Schraufnagel³

et al. 1995

Am J Respir Cell Mol Biol

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Alveolar macrophages protect the lungs against noxious agents. Proteases and peptidases are essential for this defense and many metabolic activities. Human alveolar macrophages were evaluated for the presence of six important peptidases. Deamidase, a serine peptidase identical with the lysosomal protective protein and possibly with cathepsin A, had high specific activity in alveolar macrophages and is also present in cultured mouse J774A.1 and human U937 cells, used for the sake of comparison. In fractionated J774A cells, most of the deamidase activity was in the lysosomal fraction and in the final supernatant. Deamidase in human alveolar macrophages, obtained by bronchoalveolar lavage from 23 patients, cleaved dansyl-Phe-Leu-Arg at a rate of 2.26 mumol/h/mg protein and hydrolyzed the chemotactic peptide N-f-Met-Leu-Phe even faster, at a rate of 53.1 mumol/h/mg protein, the highest activity for this enzyme with any of the cells we tested. Rabbit antiserum, elicited with the recombinant partial sequence of the enzyme, immunoprecipitated 77-88% of the macrophage deamidase. In immunocytochemistry, this antiserum localized deamidase within the human macrophages. The enzyme was inhibited by diisopropylfluorophosphate (DFP; 1 mM) and by ebelactone B (10 microM), noncompetitively. The mRNA of deamidase was detected in mouse macrophages by Northern blot; the two protein chains of deamidase were shown in human macrophages by Western blot. In addition, two other serine peptidases were also highly active in macrophages: dipeptidyl peptidase IV (1.38 mumol/h/mg protein) and prolylcarboxypeptidase (0.72 mumol/h/mg protein). The activity of plasma membrane zinc metallopeptidases, neutral endopeptidase 24.11 and carboxypeptidase M, in contrast, was low or absent (angiotensin I converting enzyme; kininase II).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Plasma membrane-bound and lysosomal peptidases in human alveolar macrophages.

Jackman¹,

Tan²,

Schraufnagel³

et al. 1995

Am J Respir Cell Mol Biol

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“…We interpret the much greater and persistent effect on bradykinin responses as being due to the higher concentration of drug in the pericardial sac, and that bradykinin in the pericardial sac mainly acts on the heart. While bradykinin elicits a neural response from lung tissue with a small bolus injection, bradykinin released from the pericardial sac in the present experiment would likely be broken down by peptidases in the lungs (Dragovic et al 1993). We also attempted to verify a lung specific effect using lung hyperinflation, but the results as to whether that stimulus only influenced the lungs were unclear.…”

Section: Differentiation Of Cardiac and Pulmonary Stimulimentioning

confidence: 93%

Characterization of thoracic spinal neurons with noxious convergent inputs from heart and lower airways in rats

2007

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Respiratory symptoms experienced in some patients with cardiac diseases may be due to convergence of noxious cardiac and pulmonary inputs onto neurons of the central nervous system. For example, convergence of cardiac and respiratory inputs onto single solitary tract neurons may be in part responsible for integration of regulatory and defensive reflex control. However, it is unknown whether inputs from the lungs and heart converge onto single neurons of the spinal cord. The present aim was to characterize upper thoracic spinal neurons responding to both noxious stimuli of the heart and lungs in rats. Extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed, and ventilated male rats. A catheter was placed in the pericardial sac to administer bradykinin (BK, 10 μg/ml, 0.2 ml, 1 min) as a noxious cardiac stimulus. The lung irritant, ammonia, obtained as vapor over a 30% solution of NH 4 OH was injected into the inspiratory line of the ventilator (0.5-1.0 ml over 20 sec). Intrapericardial bradykinin (IB) altered activity of 58/65 (89%) spinal neurons the responded to inhaled ammonia (IA). Among those cardiopulmonary convergent neurons, 81% (47/58) were excited by both IA and IB, and the remainder had complex response patterns. Bilateral cervical vagotomy revealed that vagal afferents modulated but did not eliminate responses of individual spinal neurons to IB and IA. The convergence of pulmonary and cardiac nociceptive signaling in the spinal cord may be relevant to situations where a disease process in one organ influences the behavior of the other.

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“…Second, several lines of evidence suggest that BK metabolism in tissues and in the circulation may differ. Thus in tissues such as the kidneys 25 and lungs, 26,27 NEP plays a significant role, along with ACE, in BK metabolism. Interestingly, in in vitro experiments with skeletal muscle, BK was degraded by NEP but not by ACE.…”

Section: Role Of Ace In Bradykinin Metabolismmentioning

confidence: 99%

Kallidin- and Bradykinin-Degrading Pathways in Human Heart

et al. 1999

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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 (nϭ5) and failing (nϭ10) 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. (Circulation. 1999;99:1984-1990.)

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Metabolism of Bradykinin by Peptidases in the Lung

Cited by 38 publications

References 36 publications

Plasma membrane-bound and lysosomal peptidases in human alveolar macrophages.

Plasma membrane-bound and lysosomal peptidases in human alveolar macrophages.

Characterization of thoracic spinal neurons with noxious convergent inputs from heart and lower airways in rats

Kallidin- and Bradykinin-Degrading Pathways in Human Heart

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