Document Detail


Vasoconstrictor effect of the angiotensin-converting enzyme-resistant, chymase-specific substrate [Pro(11)(D)-Ala(12)] angiotensin I in human dorsal hand veins: in vivo demonstration of non-ace production of angiotensin II in humans.
MedLine Citation:
PMID:  11591618     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: [Pro(11)(D)-Ala(12)] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II-generating pathway exists in human dorsal hand veins. METHODS AND RESULTS: Using a modified Aellig technique, we studied the response to Ang I and [Pro(11)(D)-Ala(12)] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean+/-SEM venoconstrictor response of 45+/-11%, 40+/-10%, 55+/-8%, and 4+/-4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P=0.002). [Pro(11)(D)-Ala(12)] Ang I induced a mean venoconstrictor response of 42+/-9%, 49+/-9%, 48+/-10%, and 54+/-11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro(11)(D)-Ala(12)] Ang I. CONCLUSIONS: We have demonstrated that [Pro(11)(D)-Ala(12)] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.
Authors:
J E McDonald; N Padmanabhan; M C Petrie; C Hillier; J M Connell; J J McMurray
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Publication Detail:
Type:  Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  104     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-09     Completed Date:  2001-12-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1805-8     Citation Subset:  AIM; IM    
Affiliation:
CRI in Heart Failure, Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Angina Pectoris / drug therapy,  physiopathology*
Angiotensin I / analogs & derivatives*,  metabolism,  pharmacology*
Angiotensin II / biosynthesis
Angiotensin-Converting Enzyme Inhibitors / administration & dosage
Antihypertensive Agents / administration & dosage
Biphenyl Compounds / administration & dosage
Captopril / administration & dosage
Chronic Disease
Chymases
Dose-Response Relationship, Drug
Double-Blind Method
Hand / blood supply
Humans
Infusions, Intravenous
Middle Aged
Peptidyl-Dipeptidase A / metabolism
Receptors, Angiotensin / antagonists & inhibitors
Reproducibility of Results
Serine Endopeptidases / metabolism
Substrate Specificity
Tetrazoles / administration & dosage
Vasoconstriction / drug effects*
Veins / drug effects*,  physiopathology*
Chemical
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Antihypertensive Agents; 0/Biphenyl Compounds; 0/Receptors, Angiotensin; 0/Tetrazoles; 0/angiotensin I, Pro(11)-Ala(12)-; 11128-99-7/Angiotensin II; 138402-11-6/irbesartan; 62571-86-2/Captopril; 9041-90-1/Angiotensin I; EC 3.4.15.1/Peptidyl-Dipeptidase A; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.39/Chymases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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