Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man.
OBJECTIVE
Angiotensin II and bradykinin are potent endogenous vasoactive peptides which may play a role in the regulation of endogenous fibrinolysis and, thereby, contribute to the beneficial actions of ACE inhibitors. The aims of the study were to determine the acute effect of angiotensin II and bradykinin on the local vascular release of tissue plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), and the endothelium-derived haemostatic factor, von Willebrand factor (vWf) from the forearm.


METHODS
Blood flow, and plasma haemostatic and fibrinolytic factors, were measured in both forearms of sixteen healthy men: eight subjects received intra-arterial angiotensin II (5, 50 and 500 pmol/min) which was coinfused with sodium nitroprusside (SNP; 0.3, 1.5 and 7.5 microg/min, respectively), and eight received intra-arterial bradykinin at 10-3000 pmol/min.


RESULTS
Despite substantial rises in plasma angiotensin II concentrations (P<0.001) which caused pressor effects (P<0.003) at the highest dose, angiotensin II infusion did not affect local plasma t-PA, PAI-1 or vWf concentrations. In contrast, bradykinin caused substantial dose-dependent increases in blood flow and t-PA release (>100 ng/100 ml of tissue/min) in the infused forearm (P<0. 001 for both) without affecting plasma PAI-1 or vWf concentrations.


CONCLUSIONS
Despite high local concentrations with breakthrough of significant systemic effects, angiotensin II did not affect acute endothelial cell t-PA, PAI-1 or vWf release in healthy men. In contrast, bradykinin is a potent vasodilator and selective stimulus for acute local t-PA release. This may, at least in part, explain the fibrinolytic actions of ACE inhibitors in heart failure and ischaemic heart disease.
Labinjoh
C
C
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK.
Newby
D E
DE
Dawson
P
P
Johnston
N R
NR
Ludlam
C A
CA
Boon
N A
NA
Webb
D J
DJ
D000328:Adult; D000704:Analysis of Variance; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D013268:Stimulation, Chemical; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014841:von Willebrand Factor / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D014665:Vasodilator Agents; D014841:von Willebrand Factor; D000804:Angiotensin II; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D001920:Bradykinin