Distinct roles for PAR1- and PAR2-mediated vasomotor modulation in human arterial and venous conduits.
BACKGROUND
Patency rates after coronary artery bypass grafting (CABG) are better if the internal mammary artery (IMA) is used rather than the greater saphenous vein (GSV), and may be related to the endothelial release of vasodilators antagonizing vascular contraction. It has recently been shown that a family of protease-activated receptors (PARs) modulate endothelium-dependent vasodilatation.


OBJECTIVE
The aim of this study was to evaluate the presence and functional role of protease-activated receptor 1 (PAR1) and protease-activated receptor 2 (PAR2) in mediating vascular tone in IMAs and GSVs from patients undergoing CABG by means of real time-PCR and isometric tension measurements.


RESULTS
PAR1 mRNA levels were higher than those of PAR2 mRNA in both vessels. A selective PAR2-activating peptide (PAR2-AP), SLIGKV-NH(2) (0.01-100 micromol L(-1)), failed to induce vasorelaxation in precontracted IMA and GSV rings, whereas the selective PAR1-AP, TFLLR-NH(2) (0.001 to 10 micromol L(-1)), caused greater endothelium-dependent relaxation in the IMAs (pD(2) values 7.25 +/- 0.6 vs. 7.86 +/- 0.42, P < 0.05; E(max) values 56.2 +/- 17.3% vs. 29.7 +/- 13.4%, P < 0.001). Preincubation with TNFalpha (3 nmol L(-1)) induced vasorelaxation in IMAs in response to PAR2-AP (P < 0.05 vs. non-stimulated vessels); the response to PAR1-AP was unchanged. The relaxation induced by both PAR-APs was NO- and endothelium-dependent.


CONCLUSIONS
These data show that functionally active PAR1 and PAR2 are present in IMAs and GSVs, and that inflammatory stimuli selectively enhance endothelium-dependent relaxation to PAR2-AP in IMAs.
Ballerio
R
R
Department of Cardiac Surgery, Centro Cardiologico Monzino IRCCS, Milan, Italy.
Brambilla
M
M
Colnago
D
D
Parolari
A
A
Agrifoglio
M
M
Camera
M
M
Tremoli
E
E
Mussoni
L
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001026:Coronary Artery Bypass / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D012107:Research Design; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D009842:Oligopeptides; C462999:PAR-1-activating peptide; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha; C515807:seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide; D009569:Nitric Oxide