Nitric oxide donating aspirins: novel drugs for the treatment of saphenous vein graft failure.
BACKGROUND
A new class of nitric oxide donating aspirin (NO-ASA) drugs may increase the therapeutic impact of aspirin in saphenous vein coronary artery bypass grafting (CABG) not only through the inhibition of thrombosis but also through a reduction of vasospasm and inhibition of vascular smooth muscle cell (VSMC) proliferation (effects that are inhibited by NO but not ASA). In order to test this proposal the effect of three NO-ASA drugs (NCX4040, NCX4050, and NCX4060) on in vitro relaxation and cyclic guanosine monophosphate (cGMP) formation in the human isolated saphenous vein and the proliferation of human VSMCs was investigated.


METHODS
Saphenous vein segments were obtained from 30 patients undergoing CABG (median age, 59 years; range, 49 to 68). The effect of the NO-ASA adducts, ASA alone, and sodium nitroprusside (NO donor) were investigated on (1) relaxation of phenylephrine-stimulated contraction using an organ bath, (2) cyclic guanosine monophosphate (cGMP) formation using an enzyme-linked immunosorbent assay, and (3) the proliferation of VSMCs derived from saphenous vein using bromo-deoxyuridine (BRDU) incorporation.


RESULTS
All three NO-ASA adducts (at concentrations that inhibited responses by 50% [IC50s] between 1 micromol/L and 100 micromol/L) and nitroprusside (at IC50s between 0.5 and 10 micromol/L) elicited relaxation of isolated human saphenous vein, promoted cGMP formation, and inhibited VSMC proliferation whereas ASA alone (up to 100 micromol/L) had no effect on any variable.


CONCLUSIONS
These data indicate that the NO-ASA adducts by virtue of their capacity to release NO and stimulate guanylyl cyclase may be useful not only in the prevention of thrombosis following CABG but also the reduction of saphenous vein graft spasm and neointima formation.
Shukla
Nilima
N
Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom.
Angelini
Gianni D
GD
Ascione
Raimondo
R
Talpahewa
Sudath
S
Capoun
Radek
R
Jeremy
Jamie Y
JY
D000368:Aged; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D006152:Cyclic GMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D012501:Saphenous Vein / Q000187:drug effects* / Q000637:transplantation*; D014664:Vasodilation / Q000187:drug effects
D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D009599:Nitroprusside; D007770:L-Lactate Dehydrogenase; C102148:nitroaspirin; D006152:Cyclic GMP; D001241:Aspirin