title: Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition.
abstract: 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 mug/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.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom, EH16 4SB. nick.cruden@ed.ac.uk
authors.forename: Nicholas L M
authors.initials: NL
authors.lastname: Cruden
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: Neil R
authors.initials: NR
authors.lastname: Johnston
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D009320:Atrial Natriuretic Factor / Q000627:therapeutic use; D001920:Bradykinin / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009599:Nitroprusside / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use*; D043783:Receptor, Bradykinin B1 / Q000819:agonists / Q000378:metabolism; D015244:Thiorphan / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D043783:Receptor, Bradykinin B1; D014665:Vasodilator Agents; D009599:Nitroprusside; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D010959:Tissue Plasminogen Activator; D015260:Neprilysin; D001920:Bradykinin