Intravascular and interstitial degradation of bradykinin in isolated perfused rat heart
- 1 November 1997
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 122 (6), 1179-1187
- https://doi.org/10.1038/sj.bjp.0701501
Abstract
Bradykinin (BK) has been shown to exert cardioprotective effects which are potentiated by inhibitors of angiotensin I‐converting enzyme (ACE). In order to clarify the significance of ACE within the whole spectrum of myocardial kininases we investigated BK degradation in the isolated rat heart. Tritiated BK (3H‐BK) or unlabelled BK was either repeatedly perfused through the heart, or applied as an intracoronary bolus allowing determination of its elution kinetics. BK metabolites were analysed by HPLC. Kininases were identified by ramiprilat, phosphoramidon, diprotin A and 2‐mercaptoethanol or apstatin as specific inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV and aminopeptidase P (APP), respectively. In sequential perfusion passages, 3H‐BK concentrations in the perfusate decreased by 39% during each passage. Ramiprilat reduced the rate of 3H‐BK breakdown by 54% and nearly abolished [1‐5]‐BK generation. The ramiprilat‐resistant kininase activity was for the most part inhibited by the selective APP inhibitor apstatin (IC50 0.9 μM). BK cleavage by APP yielded the intermediate product [2‐9]‐BK, which was rapidly metabolized to [4‐9]‐BK by dipeptidylaminopeptidase IV. After bolus injection of 3H‐BK, 10% of the applied radioactivity were protractedly eluted, indicating the distribution of this fraction into the myocardial interstitium. In samples of such interstitial perfusate fractions, 3H‐BK was extensively (by 92%) degraded, essentially by ACE and APP. The ramiprilat‐ and mercaptoethanol‐resistant fraction of interstitial kininase activity amounted to 14%, about half of which could be attributed to NEP. Only the product of NEP, [1–7]‐BK, was continuously generated during the presence of 3H‐BK in the interstitium. ACE and APP are located at the endothelium and represent the predominant kininases of rat myocardium. Both enzymes form a metabolic barrier for the extravasated fraction of BK. Thus, only interstitial, but not intravascular concentrations of BK are increased by kininase inhibitors to the extent that a significant potentiation of BK effects could be explained. NEP contributes less than 5% to the total kininase activity, but is the only enzyme which is exclusively present in the interstitial space. British Journal of Pharmacology (1997) 122, 1179–1187; doi:10.1038/sj.bjp.0701501Keywords
This publication has 33 references indexed in Scilit:
- Degradation of bradykinin by bovine tracheal epithelium and isolated epithelial cellsBritish Journal of Pharmacology, 1997
- Regulation and Differential Expression of Neutral Endopeptidase 24.11 in Human Endothelial CellsHypertension, 1995
- Nitric Oxide Accounts for Postischemic Cardioprotection Resulting from Angiotensin-Converting Enzyme InhibitionJournal of Cardiovascular Pharmacology, 1995
- A local kallikrein-kinin system is present in rat hearts.Hypertension, 1994
- Inhibition by converting enzyme inhibitors of pig kidney aminopeptidase P.Hypertension, 1992
- Purification and characterization of guinea pig serum aminoacylproline hydrolase (aminopeptidase P)Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1992
- Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation.JCI Insight, 1990
- Hemodynamic Effects of Bradykinin on Systemic and Pulmonary Circulation in Healthy and Hypertensive HumansJournal of Cardiovascular Pharmacology, 1990
- Enzymatic heterogeneity of the capillary bed of rat skeletal musclesJournal of Anatomy, 1986
- Human kidney "enkephalinase", a neutral metalloendopeptidase that cleaves active peptidesBiochemistry, 1983