This Article Full Text Full Text (PDF) All Versions of this Article: 44/6/913    most recent 01.HYP.0000146483.78994.56v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cruden, N. L.M. Articles by Newby, D. E. Search for Related Content PubMed PubMed Citation Articles by Cruden, N. L.M. Articles by Newby, D. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Related Collections Cardio-renal physiology/pathophysiology Congestive Cardiovascular Pharmacology Fibrinolysis Other Vascular biology

(Hypertension. 2004;44:913.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Neutral Endopeptidase Inhibition Augments Vascular Actions of Bradykinin in Patients Treated With Angiotensin-Converting Enzyme Inhibition

Nicholas L.M. Cruden; Keith A.A. Fox; Christopher A. Ludlam; Neil R. Johnston; David E. Newby

From the Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, United Kingdom.

Reprint requests to Dr N.L.M. Cruden, Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK, EH16 4SB. E-mail nick.cruden{at}ed.ac.uk

Angiotensin-converting enzyme and neutral endopeptidase (EC 3.4.24.11; neprilysin) are metallopeptidases present on the endothelium that metabolize bradykinin. Inhibitors of angiotensin-converting enzyme potentiate bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. Combined angiotensin-converting enzyme and neutral endopeptidase inhibition may have additional beneficial cardiovascular effects mediated through bradykinin potentiation. We investigated the effects of local neutral endopeptidase inhibition on the vascular actions of bradykinin in heart failure patients maintained on chronic angiotensin-converting enzyme inhibition. Ten patients received intrabrachial infusion of thiorphan (30 nmol/min), a neutral endopeptidase inhibitor, in a randomized double-blind placebo-controlled crossover trial. Thiorphan was coinfused with Lys-des-Arg⁹-bradykinin (1 to 10 nmol/min), bradykinin (30 to 300 pmol/min), atrial natriuretic peptide (10 to 100 pmol/min), and sodium nitroprusside (2 to 8 µg/min). Bradykinin, atrial natriuretic peptide, and sodium nitroprusside caused dose-dependent vasodilatation (peak blood flow 14.4±2.2, 3.6±0.6, and 8.6±1.3 mL per 100 mL/min, respectively; P<0.0001). Bradykinin caused dose-dependent increases in tissue plasminogen activator antigen and activity (peak concentration 31.8±3.4 ng/mL and 21.9±7.6 IU/mL, respectively; P<0.001) and estimated antigen and activity release (peak release 152±46 ng per 100 mL/min and 154±22 IU/100 mL/min, respectively; P<0.005). Compared with placebo, thiorphan augmented bradykinin-mediated vasodilatation (1.4-fold; P<0.0001) and net tissue plasminogen activator release (1.5-fold; P<0.005). Neutral endopeptidase contributes to bradykinin metabolism in heart failure patients maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the clinical effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition, including the greater vasodepressor effect observed with combined therapy when compared with angiotensin-converting enzyme inhibition alone.

Key Words: heart failure • angiotensin-converting enzyme • bradykinin • endothelium

This article has been cited by other articles:

				A. Fleischmann, T. Schlomm, H. Huland, J. Kollermann, P. Simon, M. Mirlacher, G. Salomon, F. H.K. Chun, T. Steuber, R. Simon, et al. Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients Clin. Cancer Res., December 1, 2008; 14(23): 7838 - 7842. [Abstract] [Full Text] [PDF]

				A. Maloyan, J. Gulick, C. G. Glabe, R. Kayed, and J. Robbins Exercise reverses preamyloid oligomer and prolongs survival in {alpha}B-crystallin-based desmin-related cardiomyopathy PNAS, April 3, 2007; 104(14): 5995 - 6000. [Abstract] [Full Text] [PDF]

				J. J. Oliver, D. J. Webb, and D. E. Newby Stimulated Tissue Plasminogen Activator Release as a Marker of Endothelial Function in Humans Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2470 - 2479. [Abstract] [Full Text] [PDF]