Endothelial action of thienopyridines and thienopyrimidinones in the isolated guinea pig heart.
Antiplatelet thienopyridines (ticlopidine, clopidogrel) and their thienopyrimidinone congeners, induce prostacyclin-dependent thrombolysis in vivo. Here we tested whether thienopyridines (ticlopidine, clopidogrel, and its enantiomer without antiplatelet properties) and structurally related thienopyrimidinones release NO from coronary endothelium in the isolated guinea pig heart, perfused according to Langendorff technique. The involvement of endothelium-derived NO in coronary vasodilation induced by these agents was assessed by effect of L-N(G)-nitro-arginine methyl ester (L-NAME). In addition, effect of thienopyridines or thienopyrimidinones on nitrite accumulation in cultured endothelium was assayed. Tienopyridines (10-100 micromol L(-1)) and thienopyrimidinones (10-30 micromol L(-1)) produced concentration-dependent increase in coronary flow comparable to that induced by acetylcholine (0.1 micromol L(-1)) or bradykinin (3 nmol L(-1)) which was inhibited by L-NAME (by 50-70%) but not by indomethacin. Furthermore, thienopyridines and thienopyrimidinones caused NO release from cultured endothelial cells. In conclusion, both thienopyridines independently from their antiplatelet action and their thienopyrimidinone congeners that are devoid of antiplatelet action stimulate coronary endothelium to release NO. Endothelial action of these compounds merits further investigation.
Jakubowski
A
A
Department of Experimental Pharmacology, Jagiellonian University School of Medicine, ul. Grzegorzecka 16, 31-531 Krakow, Poland.
Chlopicki
S
S
Olszanecki
R
R
Jawien
J
J
Lomnicka
M
M
Dupin
J P
JP
Gryglewski
R J
RJ
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C446540:thienopyridine; C476003:thienopyrimidine; D009569:Nitric Oxide